Antipicornaviral compounds and compositions, their pharmaceutical uses, and materials for their synthesis

ABSTRACT

Compounds of the formula:  
                 
 
     where the formula variables are as defined in the disclosure, advantageously inhibit or block the biological activity of the picornaviral 3C protease. These compounds, as well as pharmaceutical compositions containing these compounds, are useful for treating patients or hosts infected with one or more picornaviruses, such as RVP. Intermediates and synthetic methods for preparing such compounds are also described.

[0001] This application claims benefit of U.S. Provisional PatentApplication No. 60/211,424, filed Jun. 14, 2000.

BACKGROUND OF THE INVENTION

[0002] 1. Field of the Invention

[0003] The invention relates to compounds that advantageously inhibitthe enzymatic activity of picornaviral 3C proteases, especiallyrhinovirus 3C proteases (RVPs), and that retard viral growth in cellculture. The invention also relates to the use of such compounds inpharmaceutical compositions and therapeutic treatments for rhinoviralinfections. The invention further relates to processes for synthesizingsuch compounds and intermediate compounds useful in such syntheses.

[0004] 2. Related Background Art

[0005] The picornaviruses are a family of tiny non-envelopedpositive-stranded RNA-containing viruses that infect humans and otheranimals. These viruses include the human rhinoviruses, humanpolioviruses, human coxsackieviruses, human echoviruses, human andbovine enteroviruses, encephalomyocarditis viruses, meningitis virus,foot and mouth viruses, hepatitis A virus, and others. The humanrhinoviruses are a major cause of the common cold. To date, there are noeffective therapies that cure the common cold, only treatments thatrelieve the symptoms.

[0006] Picornaviral infections may be treated by inhibiting theproteolytic 3C enzymes. These enzymes are required for the naturalmaturation of the picornaviruses. They are responsible for theautocatalytic cleavage of the genomic, large polyprotein into theessential viral proteins. Members of the 3C protease family are cysteineproteases, where the sulfhydryl group most often cleaves theglutamine-glycine amide bond. Inhibition of 3C proteases is believed toblock proteolytic cleavage of the polyprotein, which in turn can retardthe maturation and replication of the viruses by interfering with viralparticle production. Therefore, inhibiting the processing of thiscysteine protease with selective molecules that are specificallyrecognized should represent an important and useful approach to treatand cure viral infections of this nature and, in particular, the commoncold.

[0007] Some inhibitors of the enzymatic activity of picornaviral 3Cproteases (i.e., antipicornaviral compounds) have been recentlydiscovered. See, for example: U.S. Pat. No. 5,856,530; U.S. Pat. No.5,962,487; U.S. patent application No. 08/991,282, filed Dec. 16, 1997,by Dragovich et al.; and U.S. patent application No. 09/301,977, filedApr. 29, 1999, by Dragovich et al. See also: Dragovich et al.,“Structure-Based Design, Synthesis, and Biological Evaluation ofIrreversible Human Rhinovirus 3C Protease Inhibitors . . . , ” J. Med.Chem. (1999), Vol. 42, No. 7, 1203-1212, 1213-1224; and Dragovich etal., “Solid-phase Synthesis of Irreversible Human Rhinovirus 3C ProteaseInhibitors . . . ,” Bioorg. & Med. Chem. (1999), Vol. 7, 589-598. Thereis still a desire, however, to discover compounds that are especiallypotent antipicornaviral agents.

SUMMARY OF THE INVENTION

[0008] The present invention relates to compounds of the general formulaI:

[0009] wherein:

[0010] R^(a) may be selected from an aryl, heteroaryl, alkyl, alkenyl,amino, cycloalkyl or heterocycloalkyl group, provided that R^(a) is notpyrrolidinyl, where the aryl, heteroaryl, alkyl, alkenyl, amino,cycloalkyl or heterocycloalkyl group is unsubstituted or substitutedwith one or more suitable substituents;

[0011] R^(c) is a substituent having the formula:

[0012] wherein:

[0013] R^(f) and R^(g) are each independently H or lower alkyl;

[0014] m is 0 or 1;

[0015] p is an integer of from 0 to 5;

[0016] A₁ is CH or N;

[0017] when p is 1, 2, 3, 4, or 5, A₂ is C(R^(h))(R^(i)), N(R^(j)), S,S(O), S(O)₂, or O, and when p is 0, A₂ is C(R^(h))(R^(i))(R^(j)),N(R^(i))(R^(j)), S(R^(i)), S(O)(R^(i)), S(O)₂(R^(i)), or O(R^(i)), whereeach R^(h), R^(i) and R^(j) is independently H or a lower alkyl group;

[0018] each A₃ present is independently C(R^(h))(R^(i)), N(R^(j)), S,S(O), S(O)₂, or O; where each R^(h), R^(i) and R^(j) is independently Hor lower alkyl;

[0019] when p is 1, 2, 3, 4, or 5, A₄ is N(R^(k)), C(R^(h))(R^(i)), orO; and when p is 0 (i.e., A₃ is not present), A₄ is N(R^(k))(R^(l)),C(R^(h))(R^(i))(R^(j)), and O(R^(l)), where each R^(h), R^(i) and R^(j)is independently H or lower alkyl, each R^(k) is H, alkyl, aryl, oracyl, and each R^(l) is H, alkyl, or aryl;

[0020] provided that no more than two heteroatoms occur consecutively inthe above-depicted ring formed by A₁, (A₂)_(m), (A₃)_(p), A₄, and C═O,where each dotted line in the ring depicts a single bond when A₂ ispresent (i.e., m=1) and a hydrogen atom when A₂ is absent (i.e., m=0);

[0021] R^(d) is H, halogen, hydroxyl or an alkyl, alkoxy or alkylthiogroup, where the alkyl, alkoxy or alkylthio group is unsubstituted orsubstituted with one or more suitable substituents;

[0022] R^(b) is H or an alkyl group, unsubstituted or substituted withone or more suitable substituents;

[0023] Z and Z¹ are each independently H, F, an alkyl, cycloalkyl,heterocycloalkyl, aryl or heteroaryl group, where the alkyl, cycloalkyl,heterocycloalkyl, aryl or heteroaryl group is unsubstituted orsubstituted with one or more suitable substituents, —C(O)R^(n) —CO₂R^(n)—CN, —C(O)NR^(n)R^(o), —C(O)NR^(n)OR^(o), —C(S)R^(n), —C(S)OR^(n)—C(S)NR^(n)R^(o), —C(═NR^(n))R^(o), —C(═NR^(n))OR^(o), —NO₂, —SOR^(o),—SO₂R^(n), —SO₂NR^(n)R^(o), —SO₂(NR^(n))(OR^(o)), —SONR^(n), —SO₃R^(n),—PO(OR^(n))₂, —PO(OR^(n))(OR^(o)), —PO(NR^(n)R^(o))(OR^(p)),—PO(NR^(n)R^(o))(NR^(p)R^(q)), —C(O)NR^(n)NR^(o)R^(p),—C(S)NR^(n)NR^(o)R^(p), where R^(n), R^(o), R^(p) and R^(q) are eachindependently H or an alkyl, cycloalkyl, aryl, heterocycloalkyl, acyl orthioacyl group, where the alkyl, cycloalkyl, aryl, heterocycloalkyl,acyl or thioacyl group is unsubstituted or substituted with one or moresuitable substituents, or where any two of the R^(n), R^(o), R^(p) andR^(q), taken together with the atoms to which they are bonded, form aheterocycloalkyl group, which may be optionally substituted,

[0024] or Z and R^(d), together with the atoms to which they are bonded,form a cycloalkyl or heterocycloalkyl group, where Z and R^(d) are asdefined above except for moieties that cannot form the cycloalkyl orheterocycloalkyl group,

[0025] or Z and Z¹, together with the atoms to which they are bonded,form a cycloalkyl or heterocycloalkyl group, where Z and Z¹ are asdefined above (except for moieties that cannot form the cycloalkyl orheterocycloalkyl group); and

[0026] In another embodiment of the compounds of the above Formula I,

[0027] A₁ is CH or N; A₂ is C(R^(h))(R^(i)), N(R^(j)), S, S(O), S(O)₂,or O; where each R^(h), R^(i) and R^(j) is independently H or loweralkyl; each A₃ present is independently C(R^(h))(R^(i)), N(R^(j)), S,S(O), S(O)₂, or O; where each R^(h), R^(i) and R^(j) is independently Hor lower alkyl; when p is 1, 2, 3, 4, or 5, A₄ is N(R^(k)),C(R^(h))(R^(i)), or O; and when p is 0 (i.e., A₃ is not present), A₄ isN(R^(k))(R^(l)), C(R^(h))(R^(i))(R^(j)), and O(R^(l)), where each R^(h),R^(i) and R^(j) is independently H or lower alkyl, each R^(k) is H,alkyl, aryl, or acyl, and each R^(l) is H, alkyl, or aryl; provided thatno more than two heteroatoms occur consecutively in the above-depictedring formed by A₁, (A₂)_(m), (A₃)_(p), A₄, and C═O, where each dottedline in the ring depicts a single bond when A₂ is present (i.e., m=1)and a hydrogen atom when A₂ is absent (i.e., m=0); and Z and Z¹ are eachindependently H, F, a unsubstituted or substituted alkyl group,cycloalkyl group, heterocycloalkyl group, aryl group or heteroarylgroup, —C(O)R^(n), —CO₂R^(n), —CN, —C(O)NR^(n)R^(o), —C(O)NR^(n)OR^(o),—C(S)R^(n), —C(S)NR^(n)R^(o), —NO₂, —SOR^(o), —SO₂R^(n),—SO₂NR^(n)R^(o), —SO₂(NR^(n))(OR^(o)), —SONR^(n), —SO₃R^(n),—PO(OR^(n))₂, —PO(OR^(n))(OR^(o)), —PO(NR^(n)R^(o))(OR^(p)),—PO(NR^(n)R^(o))(NR^(p)R^(q)), —C(O)NR^(n)NR^(o)R^(p),—C(S)NR^(n)NR^(o)R^(p), where each R^(n), R^(o), R^(p) and R^(q) areindependently H or an alkyl, cycloalkyl, aryl, heterocycloalkyl, acyl orthioacyl group, where the alkyl, cycloalkyl, aryl, heterocycloalkyl,acyl or thioacyl group is unsubstituted or substituted with one or moresuitable substituents, or where any two of the R^(n), R^(o), R^(p) andR^(q), taken together with the atoms to which they are bonded, form aheterocycloalkyl group, which may be optionally substituted, form aheterocycloalkyl group, provided that Z and Z¹ are not both H; or Z andR^(d), together with the atoms to which they are bonded, form acycloalkyl or heterocycloalkyl group, where Z and R^(d) are as definedabove except for moieties that cannot form the cycloalkyl orheterocycloalkyl group; or Z and Z¹, together with the atoms to whichthey are bonded, form a cycloalkyl or heterocycloalkyl group, where Zand Z¹ are as defined above except for moieties that cannot form thecycloalkyl or heterocycloalkyl group.

[0028] One embodiment of this invention relates to compounds useful forinhibiting the activity of picornaviral 3C proteases having thefollowing general formula:

[0029] wherein R^(a1) is a cycloalkyl, heterocycloalkyl, aryl orheteroaryl group, provided that R^(a1) is not a substitutedpyrrolidinyl, where the cycloalkyl, heterocycloalkyl, aryl or heteroarylgroup is unsubstituted or substituted with one or more suitablesubstituents; and

[0030] R^(b), R^(c), R^(d), Z and Z¹ are as defined above.

[0031] Another embodiment of this invention relates to compounds usefulfor inhibiting the activity of picornaviral 3C proteases having thefollowing general formula:

[0032] wherein R^(a2) is an alkyl, aryl or heteroaryl group, where thealkyl, aryl or heteroaryl group is unsubstituted or substituted with oneor more suitable substituents; and

[0033] R^(b), R^(c), R^(d), Z and Z¹ are as defined above.

[0034] This invention also relates to compounds useful for inhibitingthe activity of picornaviral 3C proteases having the following generalformula:

[0035] wherein R^(a3) is an aryl, heterocycloalkyl, heteroaryl orarylaminocarbonyl group, where the aryl, heterocycloalkyl, heteroaryl orarylaminocarbonyl group is unsubstituted or substituted with one or moresuitable substituents;

[0036] R^(e) is H, halogen, hydroxyl, or an alkyl, alkoxy or alkylthiogroup, where the alkyl, alkoxy or alkylthio group is unsubstituted orsubstituted with one or more suitable substituents; and

[0037] R^(b), R^(c), R^(d), Z and Z¹ are as defined above.

[0038] This invention relates to compounds useful for inhibiting theactivity of picornaviral 3C proteases having the general formula:

[0039] wherein R^(a4) is an aryloxy, heteroaryloxy, alkyloxy,cycloalkyloxy, heterocycloalkyloxy, aryl, cycloalkyl, or heteroarylgroup, where the aryloxy, heteroaryloxy, alkyloxy, cycloalkyloxy,heterocycloalkyloxy, aryl, cycloalkyl, or heteroaryl group isunsubstituted or substituted with one or more suitable substituents; and

[0040] R^(b), R^(c), R^(d), R^(e), Z and Z¹ are as defined above.

[0041] In addition to compounds of the Formulae I-V, antipicornaviralagents of the invention include prodrugs, pharmaceutically activemetabolites, and pharmaceutically acceptable salts and solvates of suchcompounds.

DETAILED DESCRIPTION OF THE INVENTION

[0042] In accordance with a convention used in the art,

[0043] is used in structural formulas herein to depict the bond that isthe point of attachment of the substituent to the backbone structure.Where chiral carbons are included in chemical structures, unless aparticular orientation is depicted, both stereoisomeric forms areintended to be encompassed.

[0044] As used herein, the term “alkyl” represents a straight- orbranched-chain saturated or unsaturated hydrocarbon, containing 1 to 10carbon atoms, that may be unsubstituted or substituted by one or more ofthe substituents described below. Exemplary alkyl substituents include,but are not limited to, methyl (Me), ethyl (Et), propyl, isopropyl,butyl, isobutyl, t-butyl, ethenyl, propenyl, butenyl, pentenyl, ethynyl,butynyl, propynyl, pentynyl, hexynyl and the like. The term “loweralkyl” refers to an alkyl group containing from 1 to 4 carbon atoms.

[0045] “Cycloalkyl” represents a group comprising a non-aromaticmonocyclic, bicyclic, or tricyclic hydrocarbon containing from 3 to 14carbon atoms that may be unsubstituted or substituted by one or more ofthe substituents described below and may be saturated or partiallyunsaturated, mono- or poly-carbocyclic ring, preferably having 5-14 ringcarbon atoms. Exemplary cycloalkyls include monocyclic rings having from3-7, preferably 3-6, carbon atoms, such as cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl and the like, that may be fullysaturated or partially unsaturated. Illustrative examples of cycloalkylgroups include the following:

[0046] “Heterocycloalkyl” represents a group comprising a non-aromatic,monovalent monocyclic, bicyclic, or tricyclic radical, which may beunsubstituted or substituted by one or more of the substituentsdescribed below and may be saturated or partially unsaturated,containing 3 to 18 ring atoms and which includes 1 to 5 hetero atomsselected from nitrogen, oxygen and sulfur, and to which may be fused oneor more cycloalkyl groups, aryl groups, or heteroaryl groups.Illustrative examples of heterocycloalkyl groups include, but are notlimited to, azetidinyl, pyrrolidyl, piperidyl, piperazinyl, morpholinyl,chromenyl, tetrahydro-2H-1,4-thiazinyl, tetrahydrofuryl, dihydrofuryl,tetrahydropyranyl, dihydropyranyl, 1,3-dioxolanyl, 1,3-dioxanyl,1,4-dioxanyl, 1,3-oxathiolanyl, 1,3-oxathianyl, 1,3-dithianyl,azabicylo[3.2.1]octyl, azabicylo[3.3.1]nonyl, azabicylo[4.3.0]nonyl,oxabicylo[2.2.1]heptyl, 1,5,9-triazacyclododecyl, and the like.Illustrative examples of heterocycloalkyl groups include the followingmoieties:

[0047] wherein R is alkyl, aryl, cycloalkyl, heterocycloalkyl, hydroxylor represents a formula of a compound of this invention.

[0048] “Aryl” represents a group comprising an aromatic, monovalentmonocyclic, bicyclic, or tricyclic radical containing from 6 to 18carbon ring atoms, which may be unsubstituted or substituted by one ormore of the substituents described below. Illustrative examples of arylgroups include the following moieties:

[0049] “Heteroaryl” represents a group comprising an aromatic monovalentmonocyclic, bicyclic, or tricyclic radical, containing 5 to 18 ringatoms, including 1 to 5 heteroatoms selected from nitrogen, oxygen andsulfur, which may be unsubstituted or substituted by one or more of thesubstituents described below. As used herein, the term “heteroaryl” isalso intended to encompass the N-oxide derivative (or N-oxidederivatives, if the heteroaryl group contains more than one nitrogensuch that more than one N-oxide derivative may be formed) of thenitrogen-containing heteroaryl groups described herein. Illustrativeexamples of heteroaryl groups include, but are not limited to, thienyl,pyrrolyl, imidazolyl, pyrazolyl, furyl, isothiazolyl, furazanyl,isoxazolyl, thiazolyl, triazolyl, pyridyl, pyrazinyl, pyrimidinyl,pyridazinyl, triazinyl, benzo[b]thienyl, naphtho[2,3-b]thianthrenyl,isobenzofuranyl, xanthenyl, phenoxathienyl, indolizinyl, isoindolyl,indolyl, indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl,naphthyridinyl, quinoxyalinyl, quinzolinyl, benzothiazolyl,benzimidazolyl, benzofuranyl, tetrahydroquinolinyl, cinnolinyl,pteridinyl, carbazolyl, beta-carbolinyl, phenanthridinyl, acridinyl,perimidinyl, phenanthrolinyl, phenazinyl, isothiazolyl, phenothiazinyl,and phenoxazinyl. Illustrative examples of N-oxide derivatives ofheteroaryl groups include, but are not limited to, pyridyl N-oxide,pyrazinyl N-oxide, pyrimidinyl N-oxide, pyridazinyl N-oxide, triazinylN-oxide, isoquinolyl N-oxide, and quinolyl N-oxide. Further examples ofheteroaryl groups include the following moieties:

[0050] wherein R is alkyl, aryl, cycloalkyl, heterocycloalkyl, hydroxylor represents a formula of a compound of this invention.

[0051] As indicated herein, the alkyl, cycloalkyl, aryl,heterocycloalkyl and heteroaryl groups may be optionally substituted byone or more substituents. The term “optionally substituted” is intendedto expressly indicate that the specified group is unsubstituted orsubstituted by one or more suitable substituents. Various groups may beunsubstituted or substituted (i.e., they are optionally substituted) asindicated. The term “substituent” or “suitable substituent” is intendedto mean any suitable substituent that may be recognized or selected,such as through routine testing, by those skilled in the art.

[0052] The term “suitable substituent” represents a substituent that isoptionally present on any of the above alkyl, aryl, cycloalkyl,heterocycloalkyl or heteroaryl groups, described herein, and is selectedfrom alkyl (except for alkyl) haloalkyl, haloaryl, halocycloalkyl,haloheterocycloalkyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl,nitro, amino, hydroxamino, cyano, halo, hydroxyl, alkoxy, alkylenedioxy,aryloxy, cycloalkoxy, heterocycloalkoxy, heteroaryloxy, alkylcarbonyl,alkyloxycarbonyl, alkylcarbonyloxy, arylcarbonyl, arylcarbonyloxy,aryloxycarbonyl, cycloalkylcarbonyl, cycloalkylcarbonyloxy,cycloalkyoxycarbonyl, heteroarylcarbonyl, heteroarylcarbonyloxy,heteroaryloxycarbonyl, heterocycloalkylcarbonyl,heterocycloalkylcarbonyloxy, heterocycloalkyoxycarbonyl, carboxyl,carbamoyl, formyl, keto (oxo), thioketo, sulfo, alkylamino,cycloalkylamino, arylamino, heterocycloalkylamino, heteroarylamino,dialkylamino, alkylaminocarbonyl, cycloalkylaminocarbonyl,arylaminocarbonyl, heterocycloalkylaminocarbonyl,heteroarylaminocarbonyl, dialkylaminocarbonyl, alkylaminothiocarbonyl,cycloalkylaminothiocarbonyl, arylaminothiocarbonyl,heterocycloalkylaminothiocarbonyl, heteroarylaminothiocarbonyl,dialkylaminothiocarbonyl, alkylsulfonyl, arylsulfonyl, alkylsulfenyl,arylsulfenyl, alkylcarbonylamino, cycloalkylcarbonylamino,arylcarbonylamino, heterocycloalkylcarbonylamino,heteroarylcarbonylamino, alkylthiocarbonylamino,cycloalkylthiocarbonylamino, arylthiocarbonylamino,heterocycloalkylthiocarbonylamino, heteroarylthiocarbonylamino,alkylsulfonyloxy, arylsulfonyloxy, alkylsulfonylamino,arylsulfonylamino, mercapto, alkylthio, arylthio, and heteroarylthiogroups, where any of the alkyl, alkylene, aryl, cycloalkyl,heterocycloalkyl, heteroaryl moieties present in the above substituentsmay be further substituted with one or more substituents selected fromnitro, amino, cyano, halo, haloalkyl, haloaryl, hydroxyl, keto,hydroxamino, alkylamino, dialkylamino, mercapto, and unsubstitutedalkyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, alkoxy, aryloxy,alkylthio or arylthio groups and where any of the aryl or heteroarylmoieties may be substituted with alkylenedioxy. Preferred “suitablesubstituents” include halo, nitro, alkyl, cycloalkyl, heterocycloalkyl,aryl, heteroaryl, arylalkyl, heteroarylalkyl, —C(O)R^(r), —C(O)OR^(r),—OC(O)R^(r), —OR^(r), —SR^(r), —C(O)NR^(s)R^(t), and —NR^(s)R^(t), whereeach R^(r), R^(s), and R^(t) are independently selected from H, alkyl,cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and each alkyl,aryl, or heteroaryl substituent may optionally be further substitutedwith one or two substituents selected from unsubstituted lower alkyl,unsubstituted lower alkoxy, nitro, halo, hydroxy or phenyl, where thephenyl group is unsubstituted or substituted with one or moresubstituents independently selected from alkyl, haloalkyl,alkylenedioxy, nitro, amino, hydroxamino, alkylamino, dialkylamino,halo, hydroxyl, alkoxy, haloalkoxy, aryloxy, mercapto, alkylthio orarylthio groups.

[0053] If the substituents themselves are not compatible with thesynthetic methods of this invention, the substituent may be protectedwith a suitable protecting group that is stable to the reactionconditions used in these methods. The protecting group may be removed ata suitable point in the reaction sequence of the method to provide adesired intermediate or target compound. Suitable protecting groups andthe methods for protecting and de-protecting different substituentsusing such suitable protecting groups are well known to those skilled inthe art; examples of which may be found in T. Greene and P. Wuts,Protecting Groups in Chemical Synthesis (3^(rd) ed.), John Wiley & Sons,NY (1999), which is incorporated herein by reference in its entirety. Insome instances, a substituent may be specifically selected to bereactive under the reaction conditions used in the methods of thisinvention. Under these circumstances, the reaction conditions convertthe selected substituent into another substituent that is either usefulin an intermediate compound in the methods of this invention or is adesired substituent in a target compound.

[0054] The terms “halogen” and “halo” represent chloro, fluoro, bromo oriodo substituents. “Heterocycle” is intended to mean a heteroaryl orheterocycloalkyl group. “Acyl” is intended to mean a —C(O)—R radical,where R is an alkyl, cycloalkyl, aryl, heterocycloalkyl or heteroarylgroup. “Acyloxy” is intended to mean an —OC(O)—R radical, where R is analkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl group.“Thioacyl” is intended to mean a —C(S)—R radical, where R is an alkyl,cycloalkyl, aryl, heterocycloalkyl or heteroaryl group. “Sulfonyl” isintended to mean an —SO₂— biradical. “Sulfenyl” is intended to mean an—SO— biradical. “Sulfo” is intended to mean an —SO₂H radical.“Sulfoxide” is intended to mean a —SO₃ ⁻ radical. “Hydroxy” is intendedto mean the radical —OH. “Amine” or “Amino” is intended to mean theradical —NH₂. “Alkylamino” is intended to mean the radical —NHR_(a),where R_(a) is an alkyl group. “Dialkylamino” is intended to mean theradical —NR_(a)R_(b), where R_(a) and R_(b) are each independently analkyl group, and is intended to include heterocycloalkyl groups, whereR_(a) and R_(b), taken together, form a heterocyclic ring that includesthe amine nitrogen. “Hydroxamino” is intended to mean the radical —N—OH.“Alkoxy” is intended to mean the radical —OR_(a), where R_(a) is analkyl group. Exemplary alkoxy groups include methoxy, ethoxy, propoxy,and the like. “Lower alkoxy” groups have alkyl moieties having from 1 to4 carbons. “Alkylenedioxy” is intended to mean the divalent radical—OR_(a)O— which is bonded to adjacent atoms on an aryl or heteroarylmoiety (e.g., adjacent atoms on a phenyl or naphthyl ring), where R_(a)is a lower alkyl group. “Alkoxycarbonyl” is intended to mean the radical—C(O)OR_(a), where R_(a) is an alkyl group. “Alkylsulfonyl” is intendedto mean the radical —SO₂R_(a), where R_(a) is an alkyl group.“Alkylaminocarbonyl” is intended to mean the radical —C(O)NHR_(a), whereR_(a) is an alkyl group. “Dialkylaminocarbonyl” is intended to mean theradical —C(O)NR_(a)R_(b), where R_(a) and R_(b) are each independentlyan alkyl group. “Mercapto” is intended to mean the radical —SH.“Alkylthio” is intended to mean the radical —SR_(a), where R_(a) is analkyl group. “Carboxyl” is intended to mean the radical —C(O)OH. “Keto”or “oxo” is intended to mean the radical ═O. “Thioketo” is intended tomean the radical ═S. “Carbamoyl” is intended to mean the radical—C(O)NH₂. “Cycloalkylalkyl” is intended to mean the radical-alkyl-cycloalkyl, where alkyl and cycloalkyl are defined as above, andis exemplified by the bonding arrangement present in the groups—CH₂-cyclohexane or —CH₂-cyclohexene. “Arylalkyl” is intended to meanthe radical -alkylaryl, where alkyl and aryl are defined as above, andis exemplified by the bonding arrangement present in a benzyl group.“Aminocarbonylalkyl” is intended to mean the radical -alkylC(O) NH₂ andis exemplified by the bonding arrangement present in the group—CH₂CH₂C(O)NH₂. “Alkylaminocarbonylalkyl” is intended to mean theradical -alkylC(O)NHR_(a), where R_(a) is an alkyl group and isexemplified by the bonding arrangement present in the group—CH₂CH₂C(O)NHCH₃. “Alkylcarbonylaminoalkyl” is intended to mean theradical -alkylNHC(O)-alkyl and is exemplified by the bonding arrangementpresent in the group —CH₂NHC(O)CH₃. “Dialkylaminocarbonylalkyl” isintended to mean the radical -alkylC(O)NR_(a)R_(b), where R_(a) andR_(b) are each independently an alkyl group. “Aryloxy” is intended tomean the radical —OR_(c), where R_(c) is an aryl group. “Heteroaryloxy”is intended to mean the radical —OR_(d), where R_(d) is a heteroarylgroup. “Arylthio” is intended to mean the radical —SR_(c), where R_(c)is an aryl group. “Heteroarylthio” is intended to mean the radical—SR_(d), where R_(d) is a heteroaryl group. The alkyl, cycloalkyl, aryl,heterocycloalkyl and heteroaryl groups and the substituents containingthese groups, as defined hereinabove, may be optionally substituted byat least one other substituent. The term “optionally substituted ” isintended to expressly indicate that the specified group is unsubstitutedor substituted by one or more suitable substituents. Various groups maybe unsubstituted or substituted (i.e., they are optionally substituted)as indicated.

[0055] If an inventive compound is a base, a desired salt may beprepared by any suitable method known in the art, including treatment ofthe free base with an inorganic acid, such as hydrochloric acid,hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and thelike, or with an organic acid, such as acetic acid, maleic acid,succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid,oxalic acid, glycolic acid, salicylic acid, pyranosidyl acid, such asglucuronic acid or galacturonic acid, alpha-hydroxy acid, such as citricacid or tartaric acid, amino acid, such as aspartic acid or glutamicacid, aromatic acid, such as benzoic acid or cinnamic acid, sulfonicacid, such as p-toluenesulfonic acid or ethanesulfonic acid, or thelike.

[0056] If an inventive compound is an acid, a desired salt may beprepared by any suitable method known to the art, including treatment ofthe free acid with an inorganic or organic base, such as an amine(primary, secondary, or tertiary); an alkali metal or alkaline earthmetal hydroxide; or the like. Illustrative examples of suitable saltsinclude organic salts derived from amino acids such as glycine andarginine; ammonia; primary, secondary, and tertiary amines; and cyclicamines, such as piperidine, morpholine, and piperazine; as well asinorganic salts derived from sodium, calcium, potassium, magnesium,manganese, iron, copper, zinc, aluminum, and lithium.

[0057] All compounds of this invention contain at least one chiralcenter and may exist as single stereoisomers (e.g., single enantiomersor diastereomers), any mixture of stereosisomers (e.g., any mixture ofenantiomers or diastereomers) or racemic mixtures thereof. All suchsingle stereoisomers, mixtures and racemates are intended to beencompassed within the broad scope of the present invention. Where thestereochemistry of the chiral carbons present in the chemical structuresillustrated herein is not specified, the chemical structure is intendedto encompass compounds containing either stereoisomer of each chiralcarbon. When used describe a particular compound, the term “opticallypure” is used herein to indicate that the compound is substantiallyenantiomerically or diastereomerically pure. Compounds that aresubstantially enantiomerically pure contain at least 90% of a singleisomer and preferably contain at least 95% of a single isomer. Compoundsthat are substantially diastereomerically pure contain at least 90% of asingle isomer of each chiral carbon center present in the diastereomer,and preferably contain at least 95% of a single isomer of each chiralcarbon. More preferably, when an optically active compound is desired,it contains at least 97.5% of a single isomer and, most preferably, atleast 99% of the single isomer. Compounds identified herein as singlestereoisomers are meant to describe compounds that are present in a formthat contains at least 90% of a single isomer. The terms “racemate” and“racemate mixture” refer to a mixture of equal amounts of enantiomericcompounds, which encompass mixtures of enantiomers and mixtures ofenantiomeric diastereomers.

[0058] The compounds of this invention may be obtained instereochemically (e.g., enantiomerically or diastereomerically ) pure orsubstantially stereochemically pure form. Such compounds may be obtainedsynthetically, according to the procedures described herein usingoptically pure or substantially optically pure materials. Alternatively,these compounds may be obtained by resolution/separation of a mixture ofstereoisomers, including racemic mixtures, using conventionalprocedures. Exemplary methods that may be useful for theresolution/separation of stereoisomeric mixtures include chromatographyand crystallization/re-crystallization. Other useful methods may befound in “Enantiomers, Racemates, and Resolutions,” J. Jacques et al.,1981, John Wiley and Sons, New York, N.Y., the disclosure of which isincorporated herein by reference. Preferred stereoisomers of thecompounds of this invention are described herein.

[0059] The compounds of this invention may also exhibit the phenomenonof tautomerism. The structural formulae herein may depicted one of thepossible tautomeric forms but it should be understood that the inventionnonetheless encompasses all tautomeric forms of the compound.

[0060] The invention also relates to prodrugs, pharmaceuticallyacceptable salts, pharmaceutically active metabolites, andpharmaceutically acceptable solvates of compounds of the Formula I, II,III, IV and V.

[0061] In the compounds of each of the above-described Formulas I to V,R^(c) is defined to provide structures where m is 1 and p is 1-5 (i.e.,both A₂ and A₃ are present), m is 0 and p is 0 (i.e., both A₂ and A₃ areabsent), m is 0 and p is 1-5 (i.e., A₂ is absent and A₃ is present) andm is 1 and p is 0 (i.e., A₂ is present and A₃ is absent). Accordingly,one of ordinary skill in the are will recognize that when both A₂ and A₃are present (m is 1 and p is 1-5), the dotted line between A₁ and A₂represents a bond and the dotted line between A₂ and A₃ represents abond and when both A₂ and A₃ are absent (m is 0 and p is 0); A₂, A₃ andthe dotted line between these substituents are not present), theremaining dotted line in the structure between A₁ and A₂ represents ahydrogen (e.g., A₁ is CH₂ or NH). In embodiments of this invention whenA₂ is absent and A₃ is present (m is 0 and p is 1-5), the dotted linebetween A₁ and A₂ represents a hydrogen and the dotted line between A₂and A₃ represents a hydrogen (e.g., A₁ is CH₂ or NH and A₃ isCH(R^(h))(R^(i)), NH(R^(j)), SH, S(O)H, S(O)₂H, or OH); and when A₂ ispresent and A₃ is absent (m is 1 and p is 0), the dotted line between A₁and A₂ represents a bond and A₂ is C(R^(h))(R^(i))(R^(j)),N(R^(i))(R^(j)), S(R^(i)), S(O)(R^(i)), S(O)₂(R^(i)), or O(R^(i)) or thedotted line between A₂ and A₃ represents a hydrogen and A₂ isCH(R^(h))(R^(i)), NH(R^(j)), SH, S(O)H, S(O)₂H, or OH. In preferredembodiments of the compounds of each of the above-described Formulas, mis 1 and p is 1 or 2 or m is 0 and p is 0 or m is 1 and p is 0. Morepreferably, when m is 1 and p is 1 or 2, A₂ and A₃ are bothC(R^(h))(R^(i)). More preferably, m is 1 and p is 1.

[0062] In especially preferred embodiments of formulas I to V, R^(c) isselected from —CH₂CH₂C(O)NH₂; —CH₂CH₂C(O)NH-alkyl; —CH₂NHC(O)CH₃; and

[0063] where n is 1 or 2. More preferably, R^(c) is —CH₂CH₂C(O)NH₂ or

[0064] Especially preferred embodiments of this invention are thosecompounds where R^(c) is

[0065] In the compounds of formulas I to V, R^(d) and each R^(b) arepreferably H. In the compounds of formulas IV and V, R^(e) is preferablyH or (C₁-C₆) alkyl.

[0066] In each of the formulas I to V, Z and Z¹ are each independentlyH, alkyl, where the alkyl is unsubstituted or substituted with one ormore suitable substituents, —CO₂ ^(n), where R^(n) is as defined above,or Z and Z¹, taken together with the atom to which they are attached,form a heterocycloalkyl group, as defined above, which may be optionallysubstituted. In one useful embodiment of the compounds of thisinvention, Z and/or Z¹ may be —C(S)OR^(n), where R^(n) is as definedabove. Such compounds may be prepared using procedures described in K.Hartke, et al., Leibigs Ann. Chem., 321-330 (1989) and K. Hartke, etal., Synthesis, 960-961 (1985). More preferably, the heterocycloalkylgroup may optionally contain O, N, S and/or P and may be substituted byone or more of oxo (keto) or thioketo. In another preferred embodimentof this invention, Z and Z¹ are each independently selected from H,lower alkyl which is unsubstituted or substituted with one or moresuitable substituents, —CO₂H, —CO₂-alkyl and —CO₂-cycloalkyl, or takentogether with the atom to which they are attached form aheterocycloalkyl group, which is optionally substituted with one or moreof keto or thioketo. In other preferred embodiments of this invention, Zand Z¹ are not both H. Most preferably, Z¹ is H or lower alkyl and Z isa —CO₂H, —CO₂-alkyl, —CO₂-alkylaryl, —CO₂-alkylheteroaryl,—CO₂-cycloalkyl group, where the lower alkyl, -alkyl, -cycloalkyl,-alkylaryl and -alkylheteroaryl moieties thereof are unsubstituted orsubstituted with one or more suitable substituents, or Z¹ and Z takentogether with the atom to which they are attached form aheterocycloalkyl group, which may be optionally substituted. Exemplary Zgroups include, but are not limited to: substituted and unsubstituted—CO₂-alkyl groups, which include straight- and branched-chain alkylgroups such as ethoxycarbonyl, t-butoxycarbonyl, isopropoxycarbonyl and(2,2-dimethylpropyl)-oxycarbonyl, where the ethoxy, t-butoxy,isopropoxy, and (2,2-dimethylpropyl)-oxy moieties thereof areunsubstituted or substituted with one or more suitable substituents; andinclude substituted and unsubstituted straight and branched-chainarylalkyl and heteroarylalkyl groups, such as benzyloxycarbonyl andpyridylmethyleneoxycarbonyl, where the benzyl and pyridylmethylenemoieties thereof are unsubstituted or substituted with one or moresuitable substituents; and include substituted and unsubstituted—CO₂-cycloalkyl groups such as cyclobutyloxycarbonyl,cyclopentyloxycarbonyl, cyclohexyloxycarbonyl and cycloheptyloxycarbonylgroups, where the cyclobutyl, cyclopentyl, cyclohexyl and cycloheptylmoieties thereof are unsubstituted or substituted with one or moresuitable substituents, or Z¹ and Z taken together with the atom to whichthey are attached form

[0067] in Formulas I to V.

[0068] In another embodiment of this invention, Z¹ is H and Z is—CO₂CH₂CH₃, —CO₂(CH(CH₃)₂), —CO₂(C(CH₃)₃), —CO₂CH₂(C(CH₃)₃),—CO₂(cyclo-C₅H₉) or Z¹ and Z taken together with the atom to which theyare attached form

[0069] In yet another embodiment of this invention, Z¹ is H and Z is—CO₂CH₂CH₃.

[0070] Specific embodiments of this invention comprise compounds havingformula II, wherein R^(a1) is a (C₃-C₈)cycloalkyl, heterocycloalkyl,aryl or heteroaryl group, wherein the (C₃-C₈)cycloalkyl,heterocycloalkyl, aryl or heteroaryl group is unsubstituted orsubstituted with one or more substituents independently selected from(C₁-C₄)alkyl, aryl(C₁-C₄)alkyl, aryl, (C₃-C₈)cycloalkyl,heterocycloalkyl, heteroaryl, halo, hydroxyl, nitro, amino,(C₁-C₄)alkylamino, di-(C₁-C₄)alkylamino, aryl(C₁-C₄)alkoxy,aryloxy(C₁-C₄)alkyl, alkylenedioxy (as a substituent for aryl orheteroaryl), aryloxy, (C₃-C₈)cycloalkoxy, heteroaryloxy,(C₁-C₄)haloalkyl, (C₁-C₄)alkoxy, (C₁-C₄)haloalkoxy, hydroxamino,(C₁-C₄)alkoxycarbonyl, (C₁-C₄)alkylcarbonylamino, (C₁-C₄)alkylcarbonyl,mercapto, alkylthio or arylthio, where the (C₁-C₄)alkyl and(C₃-C₈)cycloalkyl moieties thereof are optionally substituted by one ormore of (C₁-C₄)alkyl (except for alkyl), halo, (C₁-C₄)haloalkyl,(C₁-C₄)alkoxy, (C₁-C₄)haloalkoxy and the heterocycloalkyl, aryl orheteroaryl moieties thereof are unsubstituted or are optionallysubstituted by one or more substituents independently selected fromalkyl, haloalkyl, alkylenedioxy, nitro, amino, hydroxamino, alkylamino,dialkylamino, halo, hydroxyl, alkoxy, haloalkoxy, aryloxy, mercapto,alkylthio or arylthio groups; preferably, R^(a1) is a pyrazolyl,indolyl, chromenyl, benzofuranyl, benzothienyl, benzimidazolyl,triazolyl, quinolyl, thiazolidinyl, quinoxalinyl, phenyl or naphthylgroup, where the pyrazolyl, indolyl, chromenyl, benzofuranyl,benzothienyl, benzimidazolyl, triazolyl, quinolyl, thiazolidinyl,quinoxalinyl, phenyl or naphthyl group is unsubstituted or substitutedwith one or more substituents independently selected from (C₁-C₄)alkyl,aryl(C₁-C₄)alkyl, aryl, halo, hydroxyl, nitro, amino, (C₁-C₄)alkylamino,di-(C₁-C₄)alkylamino, (C₁-C₄)alkoxy, aryl(C₁-C₄)alkoxy,aryloxy(C₁-C₄)alkyl, methylenedioxy, aryloxy, (C₁-C₄)haloalkyl,(C₁-C₄)haloalkoxy, (C₁-C₄)alkoxycarbonyl, (C₁-C₄)alkylcarbonylamino, or(C₁-C₄)alkylcarbonyl, where the (C₁-C₄)alkyl moieties thereof areoptionally substituted by one or more of halo, (C₁-C₄)alkoxy or(C₁-C₄)haloalkoxy and the aryl moieties thereof are unsubstituted or areoptionally substituted by one or more substituents independentlyselected from alkyl, haloalkyl, alkylenedioxy, nitro, amino, alkylamino,dialkylamino, halo, hydroxyl, alkoxy, haloalkoxy or aryloxy groups; morepreferably, R^(a1) is a is a pyrazolyl, indolyl, N-methylindolyl,chromenyl, benzofuranyl, benzothienyl, benzimidazolyl, ,N-methylbenzimidazolyl, triazolyl, quinolyl, thiazolidinyl,quinoxalinyl, phenyl or naphthyl group, where the pyrazolyl, indolyl,chromenyl, benzofuranyl, benzothienyl, benzimidazolyl, triazolyl,quinolyl, thiazolidinyl, quinoxalinyl, phenyl or naphthyl group isunsubstituted or substituted with one or more substituents independentlyselected from methyl, ethyl, benzyl, phenethyl, phenyl, naphthyl, halo,hydroxyl, nitro, amino, methylamino, di-methylamino, methoxy, benzyloxy,methylenedioxy, (C₁-C₄)haloalkyl, (C₁-C₄)haloalkoxy, methoxycarbonyl,methylcarbonylamino, benzoyloxymethylene (phenylcarbonyloxymethyl-)ormethylcarbonyl;

[0071] R^(d) and each R^(b) are independently H or C₁-C₄ alkyl;preferably R^(d) and each R^(b) are H; or a prodrug, pharmaceuticallyacceptable salt, pharmaceutically active metabolite, or pharmaceuticallyacceptable solvate of said compound.

[0072] Other specific embodiments of this invention comprise thecompounds having the formula III, wherein R^(a2) is a (C₁-C₄)alkyl, arylor heteroaryl group, wherein the (C₁-C₄)alkyl, (C₃-C₈)cycloalkyl,heterocycloalkyl, aryl and heteroaryl group is unsubstituted orsubstituted with one or more suitable substituents; preferably, R^(a2)is a (C₁-C₄)alkyl, phenyl or naphthyl group, where the (C₁-C₄)alkylgroup is unsubstituted or substituted with one or more substituentsindependently selected from halo, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, C₁-C₄alkoxycarbonyl, and the phenyl or naphthyl group is unsubstituted orsubstituted with one or more substituents independently selected fromhalo, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy,methylenedioxy and phenoxy; in specific embodiments, R^(a2) is anaphthyl, phenoxyphenyl, 3,5-dimethoxy-phenyl, 3,5-dimethylphenyl or anethoxycarbonyl-substituted branched (C₁-C₆) alkyl moiety (derived fromthe ethyl ester of valine);

[0073] R^(d) and each R^(b) are independently H or C₁-C₄ alkyl;preferably R^(d) and each R^(b) are H; or a prodrug, pharmaceuticallyacceptable salt, pharmaceutically active metabolite, or pharmaceuticallyacceptable solvate of said compound.

[0074] Additional specific embodiments of this invention comprisecompounds having the formula IV, wherein R^(a3) is a aryl,heterocycloalkyl, heteroaryl or arylaminocarbonyl group, wherein thearyl, heterocycloalkyl, heteroaryl or arylaminocarbonyl group isunsubstituted or substituted with one or more substituents independentlyselected from (C₁-C₄)alkyl, aryl, halo, hydroxyl, nitro, amino,di-(C₁-C₄)alkylamino (C₁-C₄)alkoxy, alkylenedioxy (as a substituent foraryl or heteroaryl), aryloxy, where the (C₁-C₄)alkyl or aryl moietiesthereof are unsubstituted or optionally substituted by one or more of(C₁-C₄)alkyl (except for alkyl), halo, (C₁-C₄)haloalkyl, (C₁-C₄)alkoxy,(C₁-C₄)haloalkoxy, alkylenedioxy groups; in specific embodiments, R^(a3)is a phenyl or phenylaminocarbonyl group, where the phenyl group orphenyl moiety of the phenylaminocarbonyl group is unsubstituted orsubstituted with one or more substituents independently selected from(C₁-C₄)alkyl, halo, hydroxyl, nitro, (C₁-C₄)alkoxy and alkylenedioxy; inmore specific embodiments, R^(a3) is a phenyl or phenylaminocarbonylgroup, where the phenyl group or phenyl moiety of thephenylaminocarbonyl group is unsubstituted or substituted with one ormore substituents independently selected from methyl, halo, hydroxyl,nitro, methoxy, and alkylenedioxy;

[0075] R^(d), R^(e) and each R^(b) are independently H or C₁-C₄ alkyl;preferably R^(d) and each R^(b) are H; or a prodrug, pharmaceuticallyacceptable salt, pharmaceutically active metabolite, or pharmaceuticallyacceptable solvate of said compound.

[0076] Yet another specific embodiment of this invention comprisescompounds having the formula V, wherein R^(a4) is an aryloxy,heteroaryloxy, (C₁-C₄)alkoxy, (C₃-C₈)cycloalkoxy, heterocycloalkyloxy,(C₃-C₈)cycloalkyl, heteroaryl or (C₁-C₄)alkoxycarbonyl group, whereinthe aryloxy, heteroaryloxy, (C₁-C₄)alkoxy, (C₃-C₈)cycloalkoxy,heterocycloalkyloxy, (C₃-C₈)cycloalkyl, heteroaryl or(C₁-C₄)alkoxycarbonyl group is unsubstituted or substituted with one ormore substituents independently selected from (C₁-C₄)alkyl, aryl,(C₃-C₈)cycloalkyl, heterocycloalkyl, heteroaryl, halo, hydroxyl,(C₁-C₄)alkoxy, alkylenedioxy (as a substituent for aryl or heteroaryl),aryloxy, (C₃-C₈)cycloalkoxy, heteroaryloxy and (C₁-C₄)alkoxycarbonyl,where the (C₁-C₄)alkyl, aryl, (C₃-C₈)cycloalkyl, heterocycloalkyl,heteroaryl moieties thereof are optionally substituted by one or more of(C₁-C₄)alkyl (except for alkyl), halo, (C₁-C₄)haloalkyl, (C₁-C₄)alkoxy,(C₁-C₄)haloalkoxy, alkylenedioxy, aryl or heteroaryl, where the aryl orheteroaryl is unsubstituted or substituted with one or more substituentsindependently selected from alkyl, haloalkyl, alkylenedioxy, nitro,amino, hydroxamino, alkylamino, dialkylamino, halo, hydroxyl, alkoxy,haloalkoxy, aryloxy, mercapto, alkylthio or arylthio groups; in specificembodiments, R^(a4) is a phenoxy, or (C₁-C₄)alkoxycarbonyl group,wherein the phenyl moiety of the phenoxy group is unsubstituted orsubstituted with one or more substituents independently selected fromhalo and (C₁-C₄)alkoxy;

[0077] R^(d) and R^(b) are independently H or C₁-C₄ alkyl; preferablyR^(d) and each R^(b) are H;

[0078] R^(e) is H or C₁-C₆ alkyl; in specific embodiments R^(e) is H orisobutyl, or a prodrug, pharmaceutically acceptable salt,pharmaceutically active metabolite, or pharmaceutically acceptablesolvate of said compound.

[0079] In each of the above-described embodiments of the subjectinvention, R^(c) is selected from —CH₂CH₂C(O)NH₂; —CH₂CH₂C(O)NH-alkyl;—CH₂NHC(O)CH₃; and

[0080] where n is 1 or 2;

[0081] preferably, R^(c) is —CH₂CH₂C(O)NH₂ or

[0082] where n is 1;

[0083] more preferably, R^(c) is —CH₂CH₂C(O)NH₂ or

[0084] even more preferably,

[0085] R^(c) is

[0086] and

[0087] Z¹ is H or C₁-C₄ alkyl and Z is —CO₂-alkyl, —CO₂-cycloalkyl,—CO₂-alkylaryl or —CO₂-alkylheterocycloaryl, or Z¹ and Z taken togetherwith the atom to which they are attached form

[0088] preferably, Z¹ is H and Z is —CO₂CH₂CH₃, —CO₂(CH(CH₃)₂),—CO₂(C(CH₃)₃), —CO₂CH₂(C(CH₃)₃), —CO₂(cyclo-C₅H₉) or Z¹ and Z takentogether with the atom to which they are attached form

[0089] more preferably, Z¹ is H and Z is —CO₂CH₂CH₃ or Z¹ and Z takentogether with the atom to which they are attached form

[0090] even more preferably, Z¹ is H and Z is —CO₂CH₂CH₃.

[0091] The compounds have antiviral activity against picornaviruses suchas human rhinoviruses, human polioviruses, human coxsackieviruses, humanechoviruses, human and bovine enteroviruses, encephalomyocarditisviruses, meningitis virus, foot and mouth viruses, hepatitis A virus,and others. Preferably, such compounds, pharmaceutically acceptablesalts, prodrugs, active metabolites, and solvates have antipicornaviralactivity, more preferably antirhinoviral activity, corresponding to anEC₅₀ less than or equal to 100 μM in the H1-HeLa cell culture assay,more preferably corresponding to an EC₅₀ less than or equal to 10 μM inthe H1-HeLa cell culture assay.

[0092] Preferred embodiments of this invention comprise the compoundsdepicted by the formula:

[0093] where R^(a) and R^(c) are as defined above.

[0094] Other preferred embodiments of this invention comprise thecompounds depicted by the formula:

[0095] where R^(a1) and R^(c) are as defined above.

[0096] Other preferred embodiments of this invention comprise thecompounds depicted by the formula:

[0097] where R_(a2) and R^(c) are as defined above.

[0098] Other preferred embodiments of this invention comprise thecompounds depicted by the formula:

[0099] where R^(a3) and R^(c) are as defined above.

[0100] In other preferred embodiments of compounds of formula I, R^(a)is selected from:

[0101] where R^(u) and R^(v) are selected from H, F, CH₃, and C₂H₅; andR^(w), R^(x), and R^(y) are H or a substituent selected from loweralkyl, lower alkoxy, amino, halo, nitro, and hydroxy.

[0102] Yet other preferred embodiments of this invention comprise thecompounds depicted by the formula:

[0103] where R^(a4) is selected from a monosubstituted alkyl or alkoxy,where the substituent is aryl or alkyl. Particularly preferred is R^(a4)is —O-aryl or -aryl, where aryl is phenyl, unsubstituted or substitutedwith one or more suitable substituents.

[0104] Examples of preferred compounds of formula I include:

[0105] The present invention is also directed to a method of inhibitingpicornaviral 3C protease activity, comprising contacting the proteasewith an effective amount of a compound of formula I, or apharmaceutically acceptable salt, prodrug, pharmaceutically activemetabolite, or solvate thereof. For example, picornaviral 3C proteaseactivity may be inhibited in mammalian tissue by administering acompound of formula I or a pharmaceutically acceptable salt, prodrug,pharmaceutically active metabolite, or solvate thereof. More preferably,the present method is directed at inhibiting rhinoviral proteaseactivity.

[0106] A “prodrug” is intended to mean a compound that is convertedunder physiological conditions or by solvolysis or metabolically to aspecified compound that is pharmaceutically active. A prodrug may be aderivative of one of the compounds of this invention that contains amoiety, such as for example —CO₂R, —PO(OR)₂ or —C═NR, that may becleaved under physiological conditions or by solvolysis. Any suitable Rsubstituent may be used that provides a pharmaceutically acceptablesolvolysis or cleavage product. A prodrug containing such a moiety maybe prepared according to conventional procedures by treatment of acompound of this invention containing, for example, an amido, carboxylicacid, or hydroxyl moiety with a suitable reagent. A “pharmaceuticallyactive metabolite” is intended to mean a pharmacologically activecompound produced through metabolism in the body of a specifiedcompound. Prodrugs and active metabolites of compounds of this inventionof the above-described Formulas may be determined using techniques knownin the art, for example, through metabolic studies. See, e.g., “Designof Prodrugs,” (Bundgaard, ed.), 1985, Elsevier Publishers B. V.,Amsterdam, The Netherlands. A “pharmaceutically acceptable salt” isintended to mean a salt that retains the biological effectiveness of thefree acids and bases of a specified compound and that is notbiologically or otherwise undesirable. Examples of pharmaceuticallyacceptable salts include sulfates, pyrosulfates, bisulfates, sulfites,bisulfites, phosphates, monohydrogenphosphates, dihydrogenphosphates,metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates,propionates, decanoates, caprylates, acrylates, formates, isobutyrates,caproates, heptanoates, propiolates, oxalates, malonates, succinates,suberates, sebacates, fumarates, maleates, butyne-1,4-dioates,hexyne-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates,dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates,sulfonates, xylenesulfonates, phenylacetates, phenylpropionates,phenylbutyrates, citrates, lactates, γ-hydroxybutyrates, glycollates,tartrates, methane-sulfonates (mesylates), propanesulfonates,naphthalene-1-sulfonates, naphthalene-2-sulfonates, and mandelates. A“solvate” is intended to mean a pharmaceutically acceptable solvate formof a specified compound that retains the biological effectiveness ofsuch compound. Examples of solvates include compounds of the inventionin combination with water, isopropanol, ethanol, methanol, DMSO, ethylacetate, acetic acid, or ethanolamine. In the case of compounds, salts,or solvates that are solids, it is understood by those skilled in theart that the inventive compounds, salts, and solvates may exist indifferent crystal forms, all of which are intended to be within thescope of the present invention and specified formulas.

[0107] The activity of the inventive compounds as inhibitors ofpicornaviral 3C protease activity may be measured by any of the suitablemethods known to those skilled in the art, including in vivo and invitro assays. An example of a suitable assay for activity measurementsis the antiviral H1-HeLa cell culture assay described herein.

[0108] Administration of the compounds of the formula I and theirpharmaceutically acceptable prodrugs, salts, active metabolites, andsolvates may be performed according to any of the accepted modes ofadministration available to those skilled in the art. Illustrativeexamples of suitable modes of administration include oral, nasal,parenteral, topical, transdermal, and rectal. Oral and intranasaldeliveries are especially preferred.

[0109] An inventive compound of formula I or a pharmaceuticallyacceptable salt, prodrug, active metabolite, or solvate thereof may beadministered as a pharmaceutical composition in any pharmaceutical formrecognizable to the skilled artisan as being suitable. Suitablepharmaceutical forms include solid, semisolid, liquid, or lyophilizedformulations, such as tablets, powders, capsules, suppositories,suspensions, liposomes, and aerosols. Pharmaceutical compositions of theinvention may also include suitable excipients, diluents, vehicles, andcarriers, as well as other pharmaceutically active agents, dependingupon the intended use. In preferred embodiments, the inventivepharmaceutical compositions are delivered intranasally in the form ofsuspensions.

[0110] The compounds (active ingredients) may be formulated into solidoral dosage forms which may contain, but are not limited to, thefollowing active ingredients: diluents (i.e., lactose, corn starch,microcrystalline cellulose), binders (i.e., povidone, hydroxypropylmethylcellulose), disintegrants, (i.e., crospovidone, croscarmellosesodium), lubricants (i.e., magnesium stearate, stearic acid), colorants(FD&C lakes or dyes). Alternatively, the compounds may be formulatedinto other oral dosage forms including liquids, suspensions, emulsions,or soft gelatin capsules, with each dosage form having a unique set ofingredients.

[0111] Acceptable methods of preparing suitable pharmaceutical forms ofthe pharmaceutical compositions are known or may be routinely determinedby those skilled in the art. For example, pharmaceutical preparationsmay be prepared following conventional techniques of the pharmaceuticalchemist involving steps such as mixing, granulating, and compressingwhen necessary for tablet forms, or mixing, filling, and dissolving theingredients as appropriate, to give the desired products for oral,parenteral, topical, intravaginal, intranasal, intrabronchial,intraocular, intraaural, and/or rectal administration.

[0112] Solid or liquid pharmaceutically acceptable carriers, diluents,vehicles, or excipients may be employed in the pharmaceuticalcompositions. Illustrative solid carriers include starch, lactose,calcium sulfate dihydrate, terra alba, sucrose, talc, gelatin, pectin,acacia, magnesium stearate, and stearic acid. Illustrative liquidcarriers include syrup, peanut oil, olive oil, saline solution, andwater. The carrier or diluent may include a suitable prolonged-releasematerial, such as glyceryl monostearate or glyceryl distearate, alone orwith a wax. When a liquid carrier is used, the preparation may be in theform of a syrup, elixir, emulsion, soft gelatin capsule, sterileinjectable liquid (e.g., solution), or a nonaqueous or aqueous liquidsuspension.

[0113] A dose of the pharmaceutical composition contains at least atherapeutically effective amount of the active compound (i.e., acompound of formula I or a pharmaceutically acceptable salt, prodrug,active metabolite, or solvate thereof), and preferably is made up of oneor more pharmaceutical dosage units. The selected dose may beadministered to a mammal, for example, a human patient, in need oftreatment mediated by inhibition of picornaviral 3C protease activity,by any known or suitable method of administering the dose, includingtopically, for example, as an ointment or cream; orally; rectally, forexample, as a suppository; parenterally by injection; or continuously byintravaginal, intranasal, intrabronchial, intraaural, or intraocularinfusion. A “therapeutically effective amount” is intended to mean theamount of an inventive compound that, when administered to a mammal inneed thereof, is sufficient to effect treatment for disease conditionsalleviated by the inhibition of the activity of one or more picornaviral3C proteases, such as human rhinoviruses, human poliovirus, humancoxsackieviruses, encephalomyocarditis viruses, menigovirus, andhepatitis A virus. The amount of a given compound of the invention thatwill be therapeutically effective will vary depending upon factors suchas the particular compound, the disease condition and the severitythereof, the identity of the mammal in need thereof, which amount may beroutinely determined by artisans.

SYNTHESES

[0114] Examples of various preferred compounds of formula I are setforth below. The structures of the compounds of the following exampleswere confirmed by one or more of the following: proton magneticresonance spectroscopy, infrared spectroscopy, elemental microanalysis,mass spectrometry, thin layer chromatography, melting-pointdetermination, and boiling-point determination.

[0115] Proton magnetic resonance (¹H NMR) spectra were determined usinga Bruker or a Varian UNITYplus 300 spectrometer operating at a fieldstrength of 300 megahertz (MHz). Chemical shifts are reported in partsper million (ppm, δ) downfield from an internal tetramethylsilanestandard. Alternatively, ¹H NMR spectra were referenced to residualprotic solvent signals as follows: CHCl₃=7.26 ppm; DMSO=2.49 ppm;C₆HD₅=7.15 ppm. Peak multiplicities are designated as follows:s=singlet; d=doublet; dd=doublet of doublets; t=triplet; q=quartet;br=broad resonance; and m=multiplet. Coupling constants are given inHertz. Infrared absorption (IR) spectra were obtained using aPerkin-Elmer 1600 series FTIR spectrometer. Elemental microanalyses wereperformed by Atlantic Microlab Inc. (Norcross, Ga.); results of themicroanalyses are stated within ±0.4% of the theoretical values. Flashcolumn chromatography was performed using Silica gel 60 (Merck Art9385). Analytical thin layer chromatography (TLC) was performed usingprecoated sheets of Silica 60 F₂₅₄ (Merck Art 5719). Melting points(abbreviated as mp) were determined on a Mel-Temp apparatus and areuncorrected. All reactions were performed in septum-sealed flasks undera slight positive pressure of argon, unless otherwise noted. Allcommercial reagents were used as received from their respectivesuppliers.

[0116] In addition, for convenience a number of abbreviations are used.Solvents are denoted CH₃OH (methanol); DME (ethylene glycol dimethylether); DMF (N,N-dimethylformamide); DMSO (dimethylsulfoxide); Et₂O(diethyl ether); EtOAc (ethyl acetate); EtOH (ethanol); and MTBE(tert-butyl methyl ether). Certain substituents are referred to as Ac(acetyl); Me (methyl); Ph (phenyl); and Tr (triphenylmethyl). Protectinggroups are abbreviated Cbz (benzyloxycarbonyl) and Boc(tert-butoxycarbonyl).

[0117] Various reagents used were denoted BINAP(2,2-bis(diphenylphosphino)-1,1-binaphthyl); DBU(1,8-diazabicyclo[5.4.0]undec-7-ene); DCC (dicyclohexylcarbodiimide);DDQ (2,3-dichloro-5,6-dicyano-1,4-benzoquinone); DIBAH (diisobutylaluminum hydride); DIEA (N,N-diisopropylethylamine); DMAP(4-dimethylaminopyridine); EDC(1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride); HATU(O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate); HOBt (1-hydroxybenzotriazole hydrate); IBX(1,1-dihydro-1,2-benziodoxol-3(1H)-one); LiHMDS (lithiumbis(trimethylsilyl)amide); Pd-C (10% palladium on carbon); PyBOP(benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphoniumhexafluorophosphate); TBAF (tert-butyl ammonium fluoride);TBSCl-(tert-butyl dimethylsilyl chloride); and TFA (trifluoroaceticacid).

EXAMPLES Example 1 Preparation of4S-[(naphthalene-2-carbonyl)-amino]-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoicAcid Ethyl Ester

[0118]

[0119] 4S-Amino-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoic acid ethyl ester(as disclosed in U.S. patent application No. 09/301,977 which is herebyincorporated by reference in its entirety) (30 mg, 0.13 mmol) in DMF (1mL) was treated with diisopropylethyl amine (0.07 mL, 0.40 mmol),2-naphthoic acid (22 mg, 0.13 mmol), and HATU (49 mg, 0.13 mmol), andheld at room temperature for 1 h. The solution was washed with brine (5mL), and extracted with EtOAc (10 mL). Evaporation yielded 34 mg ofcrude product. Purification by preparative reverse phase chromatography(CH₃CN—H₂O) yielded 20 mg (41%) of product 1. ¹H NMR (CDCl₃) δ8.48 (1H,s), 8.01-7.85 (4H, m), 7.58-7.50 (2H, m), 6.98 (1H, dd, J=15.6, 5.3),6.04 (1H, d, J=15.8), 4.85-4.78 (1H, m), 4.17 (2H, q, J=7.0), 3.39-3.34(2H, m), 2.64-2.47 (2H, m), 2.17-2.06 (1H, m), 1.97-1.82 (3H, m), 1.34(3H, t, J=7.0). MS (FAB) 381 (MH⁺), 403 (MNa⁺).

Example 2 Preparation of4S-[(naphthalene-2-carbonyl)-amino]-5-(2-oxo-pyrrolidin-3-R-yl)-pent-2-enoicAcid Ethyl Ester

[0120]

[0121] Compound 2 was prepared by the method described in- Example 1,using 4S-amino-5-(2-oxo-pyrrolidin-3R-yl)-pent-2-enoic acid ethyl esterand 2-naphthoic acid as starting materials. ¹H NMR (CDCl₃) δ9.18 (1H, d,J=7.1), 8.46 (1H, s), 8.05-7.83(4H, m), 7.58-7.45 (2H, m), 6.99 (1H, dd,J=15.6, 4.3), 6.37 (1H, s), 6.02 (1H, dd, J=15.6, 1.5), 5.18-5.08 (1H,m), 4.17 (2H, q, J=7.1), 3.40-3.30 (2H, m), 2.72-2.60 (H, m), 2.40-2.28(1H, m), 2.20-2.00 (2H, m), 2.00-1.85 (1H, m), 1.28 (3H, t, J=7.1). MS(FAB) 381.1810 (MH⁺, calcd. 381.1814), 403 (MNa⁺).

Example 3 Preparation of4S-[3-(3-bromo-phenyl)-acryloylamino]-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoicAcid Ethyl Ester

[0122]

[0123] Compound 3 was prepared according to the method of Example 1,using 3-bromocinnamic acid. ¹H NMR (CDCl₃) δ7.67 (1H, s), 7.53 (1H, d,J=15.6), 7.50-7.38 (2H, m), 7.22 (1H, t, J=7.8), 6.89 (1H, dd, J=15.6,5.3), 6.47 (1H, d, J=15.7), 5.98 (1H, d, J=15.6), 4.74-4.63 (1H, m),4.17 (2H, q, J=7.1), 3.42-3.35 (2H, m), 2.60-2.40 (2H, m), 2.10-1.70(3H, m), 1.26 (3H, t, J=7.1). MS (FAB) 435 (MH⁺), 457 (MNa⁺).

Example 4 Preparation ofN-[3-ethoxycarbonyl-1S-(2-oxo-pyrrolidin-3R-ylmethyl)-ally]-terephthalamicAcid Methyl Ester

[0124]

[0125] Compound 4 was prepared according to the method of Example 1,using terephthalic acid methyl ester. ¹H NMR (CDCl₃) δ8.38 (1H, d,J=6.4), 8.10 (2H, d, J=8.5), 7.98 (2H, d, J=8.5), 6.92 (1H, dd, J=15.7,5.5), 6.77 (1H, s), 6.01 (1H, dd, J=15.7, 1.4), 4.85-4.74 (1H, m), 4.17(2H, q, J=7.1), 3.94 (3H, s), 3.50-3.40 (2H, m), 2.72-2.60 (1H, m),2.58-2.42 (1H, m), 2.18-2.05 (1H, m), 2.02-1.80 (2H, m), 1.27 (3H, t,J=7.1). MS (FAB) 389.1709 (MH⁺, calcd. 389.1713), 411 (MNa⁺).

Example 5 Preparation of4S-[3-(3,4-dimethoxy-phenyl)-acryloylamino]-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoicAcid Ethyl Ester

[0126]

[0127] Compound 5 was prepared according to the method of Example 1,using 3,4-dimethoxycinnamic acid. ¹H NMR (CDCl₃) δ7.58 (1H, d, J=7.0),7.34 (1H, s), 7.15-7.00 (2H, m), 6.95-6.80 (2H, m), 6.37 (1H, d,J=15.7), 5.99 (1H, J=15.5), 5.60 (1H, s), 4.88-4.70 (1H, m), 4.17 (2H,q, J=7.1), 3.90 (6H, s), 3.48-3.30 (2H, m), 2.70-2.40 (2H, m), 2.10-1.55(3H, m), 1.27 (3H, t, J=7.1). MS (FAB) 417.2008 (MH⁺, calcd. 417.2026),439 (MNa⁺).

Example 6 Preparation of4S-[(5-bromo-pyridine-3-carbonyl)-amino]-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoicAcid Ethyl Ester

[0128]

[0129] Compound 6 was prepared according to the method of Example 1,using 5-bromonicotinic acid. ¹H NMR (CDCl₃) δ9.27 (1H, d, J=5.4), 9.12(1H, s), 8.77 (1H, s), 8.45 (1H, s), 6.91 (1H, dd, J=15.6, 5.7), 6.15(1H, s), 5.99 (1H, d, J=15.7), 4.72-4.66 (1H, m), 4.18 (2H, q, J=7.1),3.42-3.38 (2H, m), 2.60-2.45 (2H, m), 2.17-1.80 (3H, m), 1.27 (3H, t,J=7.1). MS (ES) 410 (MH⁺).

Example 7 Preparation of4S-[(3-hydroxyquinoxaline-2-carbonyl)-amino]-5-(2-oxopyrrolidin-3S-yl)-pent-2-enoicAcid Ethyl Ester

[0130]

[0131] Compound 7 was prepared according to the method of Example 1,using 3-hydroxyquinoline-2-carboxylic acid. ¹H NMR (CDCl₃) δ9.80 (1H,s), 7.98 (1H, d, J=7.1), 7.50-7.30 (4H, m), 6.90 (1H, dd, J=15.6, 5.3),6.50 (1H, s), 6.01 (1H, d, J=15.6), 5.10-5.02 (1H, m), 4.17 (2H, q,J=7.1), 3.39-3.30 (2H, m), 2.60-2.47 (2H, m), 2.17-2.01 (1H, m),1.97-1.82 (2H, m), 1.27 (3H, t, J=7.1). MS (ES) 399 (MH⁺).

Example 8 Preparation of4S-[(5-ethyl-1H-indole-2-carbonyl)-amino]-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoicAcid Ethyl Ester

[0132]

[0133] Compound 8 was prepared according to the method of Example 1,using 5-ethyl-1H-indole-2-carboxylic acid. ¹H NMR (CDCl₃) δ9.15 (1H, s),8.60 (1H, d, J=5.7), 7.44 (1H, s), 7.35-7.08 (3H, m), 6.95 (1H, dd,J=15.6, 5.7), 6.04 (1H, d, J=15.6), 5.93 (1H, s), 4.75-4.70 (1H, m),4.17 (2H, q, J=7.1), 3.40-3.36 (2H, m), 2.73 (2H, q, J=7.5), 2.68-2.42(2H, m), 2.14-1.81 (3H, m), 1.33-1.24 (6H, m). MS (FAB) 398 (MH⁺), 420(MNa⁺).

Example 9 Preparation of4S-(3-benzo[1,3]dioxol-5-yl-acryloylamino)-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoicAcid Ethyl Ester

[0134]

[0135] Compound 9 was prepared according to the method of Example 1,using 3,4-methylenedioxycinnamic acid. ¹H NMR (CDCl₃) δ7.54 (1H, d,J=6.3), 7.51 (1H, d, J=15.1), 7.01 (1H, s), 6.97 (1H, d, J=8.1), 6.89(1H, dd, J=15.7, 5.3), 6.78 (1H, d, J=7.9) 6.35 (1 H, d, J=15.6),6.01-5.93 (4H, m), 4.74-4.72 (1H, m), 4.20 (2H, q, J=7.1), 3.37-3.34(2H, m), 2.53-2.42 (2H, m), 2.04-1.70 (3H, m), 1.26 (3H, t, J=7.1). MS(FAB) 423.1545 (MNa⁺, calcd. 423.1532), 423 (MNa⁺).

Example 10 Preparation of4-[(1H-benzoimidazole-2-carbonyl)-amino]-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoicAcid Ethyl Ester

[0136]

[0137] Compound 10 was prepared according to the method of Example 1,using 1H-benzoimidazole-2-carboxylic acid. ¹H NMR (CDCl₃) δ8.60 (1H, s),7.60-7.30 (5H, m), 6.90 (1H, dd, J=15.7, 5.7), 6.13 (1H, s), 6.05 (1H,d, J=15.7), 4.80-4.75 (1H, m), 4.10 (2H, q, J=7.1), 3.30-3.20 (2H, m),2.50-1.70 (5H, m), 1.27 (3H, t, J=7.1). MS (FAB) 371.1706 (MH⁺, calcd.371.1719), 393 (MNa⁺).

Example 11 Preparation of4S-[3-(4-chloro-phenyl)-acryloylamino]-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoicAcid Ethyl Ester

[0138]

[0139] Compound 11 was prepared according to the method of Example 1,using 4-chlorocinnamic acid. ¹H NMR (CDCl₃) δ7.59 (1H, s), 7.50 (1H, d,J=15.7), 7.38 (2H, d, J=8.8), 7.25 (2H, d, J=8.4), 6.79 (1H, dd, J=15.7,5.3), 6.40 (1H, d, J=15.8), 5.90 (1H, dd, J=14.2, 1.4), 5.88-5.48 (1H,s), 5.69-5.60 (1H, m), 4.10 (2H, q, J=7.1), 3.35-3.27 (2H, m), 2.58-2.37(2H, m), 1.99-1.65 (3H, m), 1.20 (3H, t, J=7.1). MS (FAB) 391.1429 (MH⁺,calcd 391.1425), 413 (MNa⁺).

Example 12 Preparation of5-(2-oxo-pyrrolidin-3S-yl)-4S-(3-p-tolyl-acryloylamino)-pent-2-enoicAcid Ethyl Ester

[0140]

[0141] Compound 12 was prepared according to the method of Example 1,using 4-methylcinnamic acid. ¹H NMR (CDCl₃) δ7.63 (1H, d, J=15.6), 7.43(2H, d, J=8.7), 7.31 (1H, d, J=7.3), 7.18 (2H, d, J=8.4), 6.97 (1H, s),6.88 (1H, d, J=15.1), 6.43 (1H, d, J=15.6), 5.99 (1H, d, J=15.7),4.84-4.77 (1H, m), 4.19 (2H, q, J=7.1), 3.46-3.48 (2H, m), 2.68-2.47(2H, m), 2.36 (3H, s), 2.11-1.71 (3H, m), 1.27 (3H, t, J=7.1). MS (FAB)371.1967 (MH⁺, calcd 371.1971) 393 (MNa⁺).

Example 13 Preparation of4S-[(3-acetyl-2-phenyl-thiazolidine-4-carbonyl)-amino]-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoicAcid Ethyl Ester

[0142]

[0143] Compound 13 was prepared according to the method of Example 1,using 3-acetyl-2-phenylthiazolidine-4-carboxylic acid. ¹H NMR (CDCl₃)δ8.07 (1H, d, J=7.0), 7.80-7.27 (5H, m), 7.10 (1H, d, J=16.0), 6.48 (1H,s), 6.20-6.05 (2H, m), 5.01 (1H, s), 4.80-4.75 (1H, m), 4.20 (2H, q,J=7.1), 3.70-3.30 (5H, m), 2.80-1.90 (4H, m), 2.15 (3H, s), 1.30 (3H, t,J=7.1). MS (FAB) 460.1894 (MH⁺,calcd. 460.1906).

Example 14 Preparation of4S-[(5-bromo-benzofuran-2-carbonyl)-amino]-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoicAcid Ethyl Ester

[0144]

[0145] Compound 14 was prepared according to the method of Example 1,using 5-bromobenzofuran-2-carboxylic acid. ¹H NMR (CDCl₃) δ7.85 (1H, d,J=7.1), 7.60 (1H, s), 7.40-7.20 (3H, m), 6.80 (1H, dd, J=15.6, 5.7),5.90 (1H, d, J=15.7), 5.60 (1H, s), 4.75-4.72 (1H, m), 4.19 (2H, q,J=7.1), 3.30-3.20 (2H, m), 2.50-2.30 (2H, m), 2.10-1.60 (3H, m), 1.27(3H, t, J=7.1). MS (FAB) 449.0696 (MH⁺, calcd 449.0712), 471 (MNa⁺).

Example 15 Preparation of4S-[3-(4-nitro-phenyl)-acryloylamino]-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoicAcid Ethyl Ester

[0146]

[0147] Compound 15 was prepared according to the method of Example 1,using 4-nitrocinnamic acid. ¹H NMR (CDCl₃) δ8.29 (1H, d, J=6.1), 8.22(2H, d, J=8.7), 7.67 (1H, d, J=14.9), 7.64 (2H, d, J=9.0), 6.88 (1H, dd,J=15.7, 5.3), 6.60 (1H, d, J=15.8), 5.98 (1H, dd, J=14.2, 1.4), 5.82(1H, s), 4.70-4.60 (1H, m), 4.17 (2H, q, J=7.1), 3.43-3.37 (2H, m),2.60-2.42 (2H, m), 2.05-1.75 (3H, m), 1.27 (3H, t, J=7.1). MS (FAB)402.1649 (MH⁺.. calcd 402.1665), 424 (MNa⁺).

Example 16 Preparation of4S-[3-(methoxy-phenyl)-acryloylamino]-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoicAcid Ethyl Ester

[0148]

[0149] Compound 16 was prepared according to the method of Example 1,using 4-methoxycinnamic acid. ¹H NMR (CDCl₃) δ7.58 (1H, d, J=15.6), 7.48(1H, d, J=7.3), 7.44 (2H, d, J=8.7), 6.90 (1H, dd, J=15.7, 5.1), 6.87(2H, d, J=8.4), 6.34 (1H, d, J=15.6), 6.07 (1H, s), 6.18 (1H, d,J=15.7), 4.80-4.65 (1H, m), 4.59 (2H, q, J=7.1), 4.11 (3H, s), 3.41-3.32(2H, m), 2.58-2.24 (2H, m), 2.08-1.68 (3H, m), 1.25 (3H, t, J=7.1). MS(FAB) 387.1927 (MH⁺, calcd 387.1920), 409 (MNa⁺).

Example 17 Preparation of4S-[3-(3-hydroxy-phenyl)-acryloylamino]-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoicAcid Ethyl Ester

[0150]

[0151] Compound 17 as prepared according to the method of Example 1,using 3-hydroxycinnamic acid as starting material. ¹H NMR (CDCl₃) δ7.77(1H, d, J=7.3), 7.57 (1H, d, J=15.6), 7.90 (1H, t, J=7.8), 7.10 (1H, s),6.90-6.81 (2H, m), 6.44 (1H, d, J=5.4), 6.42 (1H, s), 5.95 (1H, dd,J=5.7, 1.1), 4.76-4.64 (1H, m), 4.13 (2H, q, J=7.2), 3.39-3.31 (2H, m),2.58-2.37 (1H, m), 2.10-1.64 (3H, m), 1.23 (3H, t, J=7.1). MS (FAB)373.1766 (MH⁺, calcd. 373.1763), 395 (MNa⁺).

Example 18 Preparation of4S-[(6,7-dimethoxy-naphthalene-2-carbonyl)-amino]-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoicAcid Ethyl Ester

[0152]

[0153] Compound 18 was prepared according to the method of Example 1,using 6,7-dimethoxy-2-naphthoic acid. ¹H NMR (CDCl₃) δ8.30(1H, s), 8.16(1H, d, J=6.5), 7.90-7.70 (2H, m), 7.21 (s, 1H), 7.13 (s, 1H), 6.95 (1H,dd, J=15.2, 5.2), 6.43 (1H, s), 6.03 (1H, dd, J=15.7, 1.4), 4.82-4.70(1H, m), 4.17 (2H, q, J=7.1), 4.02 (3H, s), 4.00 (3H, s), 3.48-3.30 (2H,m), 2.72-2.60 (1H, m), 2.60-2.45 (1H, m), 2.20-2.05 (1H, m), 2.00-1.80(2H, m), 1.27 (3H, t, J=7.1). MS (FAB) 441.2012 (MH⁺, calcd. 441.2026),463 (MNa⁺).

Example 19 Preparation of4S-[(5,6-dimethoxy-1-methyl-indole-2-carbonyl)-amino]-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoicAcid Ethyl Ester

[0154]

[0155] Compound 19 was prepared according to the method of Example 1,using 5,6-dimethoxy-2-indolecarboxylic acid. ¹H NMR (CDCl₃) δ7.99 (1H,d, J=6.2), 7.03 (1H, s), 7.02 (1H, s), 6.95 (1H, dd, J=15.6, 5.3), 6.76(1H, s), 6.37 (1H, s), 6.03 (1H, dd, J=15.6, 1.4), 4.80-4.70 (1H, m),4.17 (2H, q, J=7.1), 4.03 (3H, s), 3.97 (3H, s), 3.91 (3H, s), 3.45-3.30(2H, m), 2.70-2.60 (1H, m), 2.60-2.45 (1H, m), 2.20-1.70 (3H, m), 1.27(3H, t, J=7.1). MS (FAB) 444.2147 (MH⁺, calcd 444.2135), 466 (MNa⁺).

Example 20 Preparation of4S-[(5-bromo-1H-indole-2-carbonyl)-amino]-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoicAcid

[0156]

[0157] Compound 20 was prepared according to the method of Example 1,using 5-bromo-2-indolecarboxylic acid. ¹H NMR (CDCl₃) δ9.94 (1H, s),8.94 (1H, d, J=5.9), 7.73 (1H, s), 7.30 (2H, s), 7.07 (1H, d, J=1.8)6.95 (1H, dd, J=15.6, 5.3), 6.42 (1H, s), 6.03 (1H, dd, J=15.6, 1.4),4.80-4.65 (1H, m), 4.17 (2H, q, J=7.1), 3.45-3.35 (2H, m), 2.70-2.55(1H, m), 2.50-2.38 (1H, m), 2.15-1.78 (3H, m), 1.27 (3H, t, J=7.1). MS(FAB) 448.0858 (MH⁺, calcd 448.0872), 470 (MNa⁺).

Example 21 Preparation of4S-[(5-bromo-1-methyl-indole-2-carbonyl)-amino]-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoicAcid Ethyl Ester

[0158]

[0159] Compound 21 was prepared according to the method of Example 1,using 5-bromo-1-methyl-2-indolecarboxylic acid. ¹H NMR (CDCl₃) δ8.69(1H, d, J=5.8), 7.76 (1H, d, J=1.8), 7.37 (1H, dd, J=8.8, 1.9), 7.23(1H, d, J=8.8), 7.07 (1H, s), 6.95 (1H, dd, J=15.6, 5.4), 6.03 (1H, dd,J=15.6, 1.4), 5.99 (1H, s), 4.72-4.60 (1H, m), 4.17 (2H, q, J=7.1), 4.04(3H, s), 3.42-3.30 (2H, m), 2.65-2.40 (2H, m), 2.20-1.70 (3H, m), 1.27(3H, t, J=7.1). MS (FAB) 462.1014 (MH⁺, calcd 462.1028), 484 (MNa⁺).

Example 22 Preparation of4S-[(3-acetylamino-naphthalene-2-carbonyl)-amino]-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoicAcid Ethyl Ester

[0160]

[0161] Compound 22 was prepared according to the method of Example 1,using 3-acetylamino-2-naphthoic acid. ¹H NMR (CDCl₃) δ11.20 (1H, s),9.30 (1H, d, J=5.4), 8.99 (1H, s), 8.31 (1H, s), 7.80 (2H, t, J=7.3),6.04 (1H, d, J=15.6), 4.70-4.65 (1H, m), 4.18 (2H, q, J=7.1), 3.19-3.15(2H, m), 2.57-2.52 (1H, m), 2.41-2.34 (1H, m), 2.22 (3H, s), 2.13-2.01(1H, m), 1.88-1.79 (2H, m), 1.27 (3H, t, J=7.1). MS (FAB) 438.2018 (MH⁺,calcd 438.2029), 460 (MNa⁺).

Example 23 Preparation of4S[3-(3-bromo-4-methyl-phenyl)-acryloylamino]-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoicAcid Ethyl Ester

[0162]

[0163] Compound 23 was prepared according to the method of Example 1,using 3-bromo-4-methylcinnamic acid. ¹H NMR (CDCl₃) δ7.81 (1H, d,J=7.0), 7.65 (1H, s), 7.52 (1H, d, J=15.6), 7.35-7.20 (2H, m), 6.89 (1H,dd, J=15.6, 5.3), 6.46 (1H, d, J=15.7), 6.15 (1H, s), 5.95 (1H, d,J=15.6), 4.78-4.65 (1H, m), 4.17 (2H, q, J=7.1), 3.40-3.30 (2H, m),2.60-2.35 (5H, m), 2.10-1.70 (3H, m), 1.27 (3H, t, J=7.1). MS (FAB)449.1090 (MH⁺, calcd 449.1076), 471 (MNa⁺).

Example 24 Preparation of4S-[3-(1S-ethoxycarbonyl-3-methyl-butyl)-ureido]-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoicAcid Ethyl Ester

[0164]

[0165] 4S-Amino-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoic acid ethyl ester(as disclosed in U.S. patent application No. 09/301,977 which is herebyincorporated by reference in its entirety) (17 mg, 0.074 mmol) in DMF (1mL) was treated with ethyl-2-isocyanato-4-methyl valerate (0.05 mL, 0.15mmol) and held at room temperature for 1 h. The solution was washed withbrine (10 mL), extracted with EtOAc (20 mL), and dried (MgSO₄).Evaporation followed by preparative reverse phase chromatography(CH₃CN—H₂O) yielded 15 mg (50%) of product 24. ¹H NMR (CDCl₃) δ6.86 (1H,dd, J=16.0, 4.9), 5.97 (1H, d, J=14.9), 4.55-4.40(2H,m), 4.28-4.10 (4H,m), 3.45-3.30 (2H, m), 2.60-2.38 (2H, m), 2.00-1.45 (6H, m), 1.32-1.23(6H, m) 0.94 (6H, d, J=0.9). HRMS (FAB) 408.2041 (MH⁺) calcd. 408.2029.

Example 25 Preparation of6-carbamoyl-4S-[(naphthalene-2-carbonyl)-amino]-hex-2-enoic Acid EthylEster

[0166]

[0167] (a) Preparation of functionalized resin

[0168] FMOC-Rink polystyrene resin (2.40 g, 1.58 mmol) (Dragovich et al.J. Med. Chem. (1998) 41:2819) was treated with a 1:1 solution ofDMF-piperidine (25 mL) to remove the FMOC. The slurry was agitated 15minutes, then washed with DMF (3×10 mL), MeOH (3×10 mL), then CH₂Cl₂(3×10 mL). The resin was then treated with a solution ofFMOC-4-amino-hept-2-enedioic acid-1-ethyl ester (1.5 eq, 2.37 mmol, 1.00g), DIEA (2 eq, 4.74 mmol, 0.82 mL), and HATU (1 eq, 2.37 mmol, 0.90 g)in DMF (25 mL). The resulting mixture was agitated 1 h, then washed withDMF (3×10 mL), MeOH (3×10 mL), then CH₂Cl₂ (3×10 mL). The FMOC wasremoved by treatment with a 2% DBU-DMF solution (25 mL), and agitated 1h. The resin was washed with CH₂Cl₂ (3×10 mL). This resin was used forall subsequent compound preparations.

[0169] (b) Conversion to Compound 25

[0170] The functionalized resin prepared above (100 mg, 0.059 mmol) wassuspended in a solution of DMF (5 mL) and DIEA (6 eq, 0.35 mmol, 0.07mL), then treated with 2-naphthoic acid (3 eq, 0.18 mmol, 34 mg) andHATU (3 eq, 0.18 mmol, 68 mg), then agitated for 2 h. The resin waswashed with CH₂Cl₂ (3×10 mL), then suspended in a 95:5 TFA- CH₂Cl₂solution (10 mL) for 1 h, with vigorous stirring. The resin was removedby filtration, and the filtrate was evaporated. The resulting oil waspurified by silica gel chromatography to yield 13 mg (63%) of product25. ¹H NMR (CDCl₃) δ8.41 (1H, s), 7.98-7.88 (4H, m), 7.62-7.53 (3H, m),6.97 (1H, dd, J=15.8, 5.0), 6.03 (1H, d, J=15.8), 4.94-4.90 (1H, m),4.19 (2H, q, J=7.0), 2.57-2.38 (2H, m), 2.17-2.11 (2H, m), 1.27 (3H, t,J=7.0). MS (FAB) 355 (MH⁺), 377 (MNa⁺).

Example 26 Preparation of4S-[(benzo[b]thiophene-2-carbonyl)-amino]-6-carbamoyl-hex-2-enoic AcidEthyl Ester

[0171]

[0172] The functionalized resin prepared in Example 25(a) was convertedto the product 26 by treatment with benzo[b]thiophene-2-carboxylic acid,as described in Example 25(b). ¹H NMR (CDCl₃) δ7.86 (1H, s), 7.84-7.76(3H, m), 7.41-7.37 (2H, m), 6.92 (1H, dd, J=15.8, 5.2), 6.00 (1H, d,J=15.8), 4.90-4.70 (1H, m), 4.17 (2H, q, J=7.2), 2.55-2.30 (2H, m),2.15-2.00 (2H, m), 1.26 (3H, t, J=7.2). MS (FAB 361 (MH⁺), 383 (MNa⁺).

Example 27 Preparation of6-carbamoyl-4S-(4-dimethylamino-benzylamino)-hex-2-enoic Acid EthylEster

[0173]

[0174] The functionalized resin prepared in Example 25(a) was convertedto the product 27 by treatment with 4-dimethylaminobenzoic acid, asdescribed in Example 25(b). ¹H NMR (CDCl₃) δ7.74 (2H, d, J=8.8), 6.93(1H, dd, J=15.6, 5.0), 5.97 (1H, d, J=15.4), 4.90-4.80 (1H, m), 4.17(2H, q, J=7.0), 3.02, (6H, s), 2.50-2.30 (2H, m), 2.20-2.00 (2H, m),1.26 (3H, t, J=7.0). MS (FAB) 386 (MH⁺), 408 (MNa⁺).

Example 28 Preparation of6-carbamoyl-4S-[(quinoxaline-2-carboxyl)-amino]-hex-2-enoic Acid EthylEster

[0175]

[0176] Compound 28 was prepared by the method of Example 25, usingquinoxaline-2-carboxylic acid. ¹H NMR (CDCl₃) δ9.62 (1H, s), 8.38-8.13(3H, m), 7.95-7.82 (2H, m), 6.95 (1H, dd, J=15.6, 5.7), 6.03 (1H, d,J=15.6), 5.95 (1H, s), 5.58 (1H, s), 5.05-4.90 (1H, m), 4.17 (2H, q,J=7.0), 2.50-2.30 (2H, m), 2.20-2.00 (2H, m), 1.25 (3H, t, J=7.1). MS(FAB) 357 (MH⁺), 379 (MNa⁺).

Example 29 Preparation of6-carbamoyl-4S-(3-phenyl-acryloylamino)-hex-2-enoic Acid Ethyl Ester

[0177]

[0178] Compound 29 was prepared by the method of Example 25, usingcinnamic acid. ¹H NMR (CD₃OD) δ7.72-7.58 (3H, m), 7.50-7.38 (3H, m),6.92 (1H, dd, J=15.6, 5.7), 6.70 (1H, d, J=15.6), 6.02 (1H, d, J=15.6),4.80-4.65 (1H, m), 4.17 (2H, q, J=7.1), 2.40-2.30 (2H, m), 2.20-1.80(2H, m), 1.25 (3H, t, J=7.1). MS (FAB) 331 (MH⁺), 353 (MNa⁺).

Example 30 Preparation of4S-[3-(3-bromophenyl)-acryloylamino]-6-carbamoyl-hex-2-enoic Acid EthylEster

[0179]

[0180] Compound 30 was prepared by the method of Example 25, using3-bromocinnamic acid. ¹H NMR (CDCl₃) δ7.80-7.20 (5H, m), 6.82 (1H, dd,J=15.6, 5.3), 6.46 (1H, d, J=15.8), 5.91 (1H, d, J=15.8), 4.75-4.60 (1H,m), 4.14 (2H, q, J=7.4), 2.40-2.20 (2H, m), 2.00-1.80 (2H, m), 1.23 (3H,t, J=7.2). MS (FAB) 409 (MH⁺), 433 (MNa⁺).

Example 31 Preparation of6-carbamoyl-4S-[(quinoline-2-carbonyl)-amino]-hex-2-enoic Acid EthylEster

[0181]

[0182] Compound 31 was prepared by the method of Example 25, usingquinoline-2-carboxylic acid. ¹H NMR (CD₃OD) δ8.40-8.10 (3H,m), 7.90-7.60(3H,m), 6.95 (1H, dd, J=15.6, 5.3), 6.03 (1H, d, J=15.6), 5.00-4.85 (1H,m), 4.18 (2H, q, J=7.1), 2.40-2.20 (2H, m), 2.00-1.80 (2H,m), 1.23 (3H,t, J=7.1). MS (FAB) 356 (MH⁺), 378 (MNa⁺).

Example 32 Preparation of6-carbamoyl-4S-[(5-methyl-2-phenyl-2H-[1,2,3]triazole-4-carbonyl)-amino]-hex-2-enoicAcid Ethyl Ester

[0183]

[0184] Compound 32 was prepared by the method of Example 25, using5-methyl-2-phenyl-2H-[1,2,3]triazole-4-carboxylic acid. ¹H NMR(CD₃OD)δ7.38-7.20 (5H, m), 6.90 (1H, dd, J=15.6, 5.3), 5.85 (1H, d, J=15.6),4.75-4.60 (1H, m), 4.18 (2H, q, J 7.1), 2.40-2.20 (2H, m), 2.00-1.80(2H, m), 1.40-1.20 (6H, m). MS (FAB) 386 (MH⁺), 408 (MNa⁺).

Example 33 Preparation of4S-[(2-benzyl-5-tert-butyl-2H-pyrazole-3-carbonyl)-amino]-6-carbamoyl-hex-2-enoicAcid Ethyl Ester

[0185]

[0186] Compound 33 was prepared by the method of Example 25, using2-benzyl-5-tert-butyl-2H-pyrazole-3-carboxylic acid. 1H NMR (CDCl₃)δ8.23 (1H,s), 8.10 (1H, d, J=7.0), 7.90-7.40 (7H, m), 6.90 (1H, dd,J=15.6, 5.3), 5.95 (1H, d, J=15.6), 4.85-4.70 (1H, m), 4.18 (2H, q,J=7.1), 2.83 (6H, s), 2.40-2.20 (2H, m), 2.10-1.90 (2H, m), 1.25 (3H, t,J=7.1). MS (FAB) 441 (MH⁺), 463 (MNa⁺).

Example 34 Preparation of 4S-benzylamino-6-carbamoyl-hex-2-enoic AcidEthyl Ester

[0187]

[0188] Compound 34 was prepared by the method of Example 25, usingbenzoic acid. ¹H NMR (CDCl₃) δ8.00-7.90 (2H, m), 7.80-7.40 (4H, m), 6.95(1H, dd, J=15.6, 5.5), 5.98 (1H, d, J=15.6), 5.95 (1H, s), 5.52 (1H, s),4.18 (2H, q, J=7.2), 2.60-2.35 (2H, m), 2.20-2.10 (2H, m), 1.25 (3H, t,J=7.1). MS (FAB) 305 (MH⁺), 327 (MNa⁺).

Example 35 Preparation of6-carbamoyl-4S-(3,4-dichloro-benzoylamino)-hex-2-enoic Acid Ethyl Ester

[0189]

[0190] Compound 35 was prepared by the method of Example 25, using3,4-dichlorobenzoic acid. ¹H NMR (CDCl₃) δ8.18 (1H, d, J=5.2), 8.03 (1H,s), 7.75 (1H, d, J=7.5), 7.52 (1H, d, J=8.0), 6.90 (1H, dd, J=15.6,5.5), 5.98 (1H, d, J=15.5), 5.80 (1H, s), 5.63 (1H, s), 4.85-4.70 (1H,m), 4.15 (2H, q, J=7.0), 2.60-2.35 (2H, m), 2.20-2.10 (2H, m), 1.25 (3H,t, J=7.1). MS (FAB) 373 (MH⁺), 395 (MNa⁺).

Example 36 Preparation of benzoicacid-2-[1S-2-carbamoyl-ethyl)-3-ethoxycarbonyl-allylcarbamoyl]-benzylEster

[0191]

[0192] Compound 36 was prepared by the method of Example 25, using2-benzoyloxymethylbenzoic acid. ¹H NMR (CDCl₃) δ8.18 (2H, m), 7.65-7.30(7H, m), 7.15 (1H, d, J=6.4), 6.95 (1H, dd, J=15.6, 5.5), 6.18 (1H, s),6.03 (1H, d, J=15.6), 5.72 (1H, d, J=12.0), 5.57 (1H, s), 5.56 (1H, d,J=12.0), 4.95-4.78 (1H, m), 4.21 (2H, q, J=7.1), 2.50-2.25 (2H, m),2.20-1.90 (2H, m), 1.28 (3H, t, J=7.1). MS (FAB) 439 (MH⁺), 461 (MNa⁺).

Example 37 Preparation of6-carbamoyl-4S-(2-phenethyl-benzoylamino)-hex-2-enoic Acid Ethyl Ester

[0193]

[0194] Compound 37 was prepared by the method of Example 25, using2-phenethylbenzoic acid. ¹H NMR (CDCl₃) δ7.42-7.10 (9H, m), 6.85 (1H,dd, J=15.5, 5.4), 6.42 (1H, d, J=6.0), 5.95 (1H, d, J=15.6), 5.90 (1H,s), 5.60 (1H, s), 4.85-4.75 (1H, m), 4.18 (2H, q, J=7.1), 3.18-2.90 (4H,m), 2.40-2.28 (2H, m), 2.10-1.90 (2H, m), 1.26 (3H, t, J=7.1). MS (FAB)409 (MH⁺), 431 (MNa⁺).

Example 38 Preparation of6-carbamyl-4S-[(1H-indole-2-carbonyl)-amino]-hex-2-enoic Acid EthylEster

[0195]

[0196] Compound 38 was prepared by the method of Example 25, usingindole-2-carboxylic acid. ¹H NMR (CDCl₃) δ9.24 (1H, s), 7.85-7.10 (6H,m), 6.95 (1H, dd, J=15.6, 5.5), 6.03 (1H, d, J=15.6), 5.68 (1H, s), 5.48(1H, s), 4.82-4.79 (1H, m), 4.21 (2H, q, J=7.1), 2.40-2.35 (2H, m),2.20-2.00 (2H, m), 1.25 (3H, t, J=7.1). MS (ES) 344 (MH⁺), 356 (MNa⁺).

Example 39 Preparation of4S-[(5-Fluoro-1H-indole-2-carbonyl)-amino]-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoicAcid Ethyl Ester

[0197]

[0198] Compound 39 was prepared according to the method of Example 1,using as starting material 5-fluoro-2-indole carboxylic acid. ¹H NMR(CDCl₃) δ9.83 (1H, s), 8.69 (1H, d, J=6.2), 7.40-7.34 (1H, m), 7.29-7.25(1H, m), 7.11 (1H, s), 7.07-7.00 (1H, m), 6.94 (1H, dd, J=16.2, 5.4),6.77 (1H, s), 6.03 (1H, d, J=15.6), 4.79-4.73 (1H, m), 4.18 (2H, q,J=7.1), 3.46-3.40 (2H, m), 2.70-2.66 (1H, m), 2.51-2.46 (1H, m),2.19-1.82 (3H, m), 1.27 (3H, t, J=7.1). MS (FAB) 388.1666 (MH⁺, calcd388.1673), 410 (MNa⁺).

Example 40 Preparation of4S-[(5-Chloro-1H-indole-2-carbonyl)-amino]-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoicAcid Ethyl Ester

[0199]

[0200] Compound 40 was prepared according to the method of Example 1,using as starting material 5-chloro-2-indole carboxylic acid. ¹H NMR(CDCl₃) δ10.22 (1H, s), 8.99 (1H, d, J=5.9), 7.54 (1H, s), 7.34 (1H, d,J=8.7), 7.17 (1H, d, J=9.1), 7.09 (1H, s), 6.96 (1H, dd, J=15.9, ), 6.58(1H, s), 6.04 (1H, d, J=15.6), 4.76-4.70 (1H, m), 4.17 (2H, q, J=7.2),3.39-3.34 (2H, m), 2.63-2.60 (1H, m), 2.46-2.41 (1H, m), 2.10-2.04 (1H,m), 1.94-1.85 (2H, m), 1.25 (3H, t, J=7.2). MS (FAB) 404.1392 (MH⁺,calcd. 404.1377), 426 (MNa⁺).

Example 41 Preparation of4S-[(5-Methoxy-1H-indole-2-carbonyl)-amino]-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoicAcid Ethyl Ester

[0201]

[0202] Compound 41 was prepared according to the method of Example 1,using as starting material 5-methoxy-2-indole carboxylic acid. ¹H NMR(CDCl₃) δ9.15 (1H, s), 8.79 (1H, d, J=5.8), 7.31 (1H, d, J=8.9), 7.07(1H, s), 7.06 (1H, s), 6.99-6.92 (2H, m), 6.04 (1H, d, J=15.6), 5.86(1H, s), 4.73-4.67 (1H, m), 4.17 (2H, q, J=7.2), 3.84 (3H, s), 3.42-3.37(2H, m), 2.63-2.57 (1H, m), 2.52-2.45 (1H, m), 2.12-1.82 (3H, m), 1.26(3H, t, J=7.1). MS (FAB) 400.1882 (MH⁺, calcd. 400.1872), 422 (MNa⁺).

Example 42 Preparation of4S-[(7-Nitro-1H-indole-2-carbonyl)-amino]-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoicAcid Ethyl Ester

[0203]

[0204] Compound 42 was prepared according to the method of Example 1,using as starting material 7-nitro-2-indole carboxylic acid. ¹H NMR(CDCl₃) δ10.55 (1H, s), 9.09 (1H, d, J=5.6), 8.26 (1H, d, J=9.1), 8.02(1H, d, J=7.8), 7.24 (1H, t, J=7.9), 6.94 (1H, dd, J=15.6, 5.7), 6.22(1H, s), 6.05 (1H, d, J=15.6), 4.76-4.70 (1H, m), 4.19 (2H, q, J=7.1),3.50-3.39 (2H, m), 2.70-2.64 (1H, m), 2.55-2.48 (1H, m), 2.14-1.86 (3H,m), 1.27 (3H, t, J=7.1). MS (FAB) 415.1636 (MH⁺, calcd. 415.1618), 437(MNa⁺).

Example 43 Preparation of4-[(5-Methyl-1H-indole-2-carbonyl)-amino]-5-(2-oxo-pyrrolidin-3-yl)-pent-2-enoicAcid Ethyl Ester

[0205]

[0206] Compound 43 was prepared according to the method of Example 1,using as starting material 5-methyl-2-indole carboxylic acid. ¹H NMR(CDCl₃) δ9.36 (1H, s), 8.52 (1H, d, J=6.3), 7.42 (1H, s), 7.32 (1H, d,J=8.3), 7.11 (1H, d, J=8.4), 7.05 (1H, s), 6.95 (1H, dd, J=15.6, 5.4),6.07 (1H, s), 6.04 (1H, d, J=16.4), 4.77-4.75 (1H, m), 4.18 (2H, q,J=7.2), 3.50-3.39 (2H, m), 2.67-2.64 (1H, m), 2.46-2.43 (1H, m), 2.43(3H, s), 2.11-2.07 (1H, m), 1.98-1.83 (2H, m), 1.27 (3H, t, J=7.1). MS(FAB) 384.1216 (MH⁺, calcd. 384.1923), 406 (MNa⁺).

Example 44 Preparation of4S-[(6-Chloro-2H-chromene-3-carbonyl)-amino]-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoicAcid Ethyl Ester

[0207]

[0208] Compound 44 was prepared according to the method of Example 1,using as starting material 6-chloro-2H-chromene-3-carboxylic acid. ¹HNMR (CDCl₃) δ8.61 (1H, d, J=5.1), 7.18-7.09 (3H, m), 6.86 (1H, dd,J=15.6, 5.6), 6.76 (1H, d, J=8.2), 5.96 (1H, d, J=15.6), 5.88 (1H, s),5.03 (2H, s), 4.60-4.50 (1H, m), 4.18 (2H, q, J=7.2), 3.43-3.36 (2H, m),2.59-2.40 (2H, m), 2.04-1.76 (3H, m), 1.27 (3H, t). MS (FAB) 419.1361(MH⁺, calcd 419.1374), 441 (MNa⁺).

Example 45 Preparation of4S-[(2-Methyl-5-phenyl-furan-3-carbonyl)-amino]-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoicAcid Ethyl Ester

[0209]

[0210] Compound 45 was prepared according to the method of Example 1,using as starting material 2-methyl-5-phenyl-furan-3-carboxylic acid. ¹HNMR (CDCl₃) δ8.16 (1H, d, J=5.8), 7.69-7.62 (2H, m), 7.42-7.34 (2H, m),7.29-7.22 (1H, m), 6.93 (1H, s), 6.92 (1H, dd, J=15.6, 5.3), 6.01 (1H,d, J=5.6), 5.68 (1H, s), 4.74-4.63 (1H, m), 4.18 (2H, q, J=7.1),3.42-3.34 (2H, m), 2.68 (3H, s), 2.62-2.42 (2H, m), 2.10-1.77 (3H, m),1.27 (3H, t). MS (FAB) 411.1929 (MH⁺, calcd 411.1920), 433 (MNa⁺).

Example 46 Preparation of4S-[(6-Benzyloxy-5-methoxy-1H-indole-2-carbonyl)-amino]-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoicAcid Ethyl Ester

[0211]

[0212] Compound 46 was prepared according to the method of Example 1,using as starting material 6-benzyloxy-5-methoxy-2-indole carboxylicacid. ¹H NMR (CDCl₃) δ9.19 (11H, s), 8.66 (1H, d, J=5.8), 7.45-6.87 (9H,m), 6.02 (1H, d, J=15.8), 5.90 (1H, s), 5.14 (2H, s), 4.71-4.67 (1H, m),4.16 (2H, q, J=7.1), 3.89 (3H, s), 3.49-3.36 (2H, m), 2.58-2.53 (1H, m),2.47-2.42 (1H, m), 2.11-1.80 (3H, m), 1.25 (3H, t, J=7.1). MS (FAB)506.2308 (MH⁺, calcd. 506.2291), 528 (MNa⁺).

Example 47 Preparation of4S-[(1H-Indole-2-carbonyl)-amino]-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoicAcid Ethyl Ester

[0213]

[0214] Compound 47 was prepared according to the method of Example 1,using as starting material 2-indole carboxylic acid. ¹H NMR (CDCl₃)δ9.38 (1H, s), 8.83 (1H, d, J=5.7), 7.65 (1H, d, J=5.8), 7.42 (1H, d,J=5.8), 7.26 (1H, t, J=5.1), 7.15 (1H, s), 7.12 (1H, t, J=5.1), 6.96(1H, dd, J=16.0, 5.4), 6.08 (1H, s), 6.04 (1H, d, J=17.0), 4.75-4.69(1H, m), 4.17 (2H, q, J=7.1), 3.41-3.36 (2H, m), 2.63-2.51 (1H, m),2.51-2.43 (1H, m), 2.18-1.82 (3H, m), 1.26 (3H, t, J=7.1). MS (FAB)370.1760 (MH⁺, calcd. 370.1767), 392 (MNa⁺).

Example 48 Preparation of4S-[3-(3-Bromo-4-fluoro-phenyl)-acryloylamino]-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoicAcid Ethyl Ester

[0215]

[0216] Compound 48 was prepared according to the method of Example 1,using as starting material 3-bromo-4-fluorocinnamic acid. ¹H NMR (CDCl₃)δ8.02 (1H, d, J=6.6), 7.71 (1H, d, J=8.6), 7.52 (1H, d, J=15.6),7.42-7.39 (1H, m), 7.11 (1H, t, J=8.3), 6.88 (1H, dd, J=15.6, 5.4), 6.41(1H, d, J=15.6), 5.97 (1H, d, J=15.7), 5.94 (1H, s), 4.75-4.61 (1H, m),4.17 (2H, q, J=7.1), 3.41-3.37 (2H, m), 2.59-2.45 (2H, m), 2.17-1.82(3H, m), 1.27 (3H, t, J=7.2). MS (FAB) 453.0812 (MH⁺, calcd. 453.0825),475 (MNa⁺).

Example 49 Preparation of4S-[3-(6-Bromo-benzo[1,3]dioxol-5-yl)-acryloylamino]-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoicAcid Ethyl Ester

[0217]

[0218] Compound 49 was prepared according to the method of Example 1,using as starting material 2-bromo-3,4-methylenedioxycinnamic acid. ¹HNMR (CDCl₃) δ7.91 (1H, d, J=15.5), 7.78 (1H, d, J=6.8), 7.05 (1H, s),7.03 (1H, s), 6.89 (1H, dd, J=15.6, 5.4), 6.29 (1H, d, J=15.5,), 6.03(2H, s), 6.01, (1H, s), 5.98 (1H, d, J=14.5), 4.72-4.67 (1H, m), 4.16(2H, q, J=7.1), 3.49-3.36 (2H, m), 2.56-2.43 (2H, m), 2.17-1.82 (3H, m),1.28 (3H, t, J=7.1). MS (FAB) 479.0807 (MH⁺, calcd 479.0818), 501(MNa⁺).

Example 50 Preparation of5-(2-Oxo-pyrrolidin-3S-yl)-4S-[3-(2,4,6-trimethyl-phenylcarbamoyl)-acryloylamino]-pent-2-enoicAcid Ethyl Ester

[0219]

[0220] Compound 50 was prepared according to the method of Example 1,using as starting material 2,4,6-trimethylphenyl maleamic acid. ¹H NMR(CDCl₃) δ6.97-6.80 (3H, m), 6.38-6.24 (2H, m), 6.06-5.93 (2H, m),4.58-4.63 (1H, m), 4.19 (2H, q, J=7.1), 3.52-3.36 (2H, m), 2.26 (3H, s),2.18 (6H, s), 2.12-1.78 (5H, m), 1.29 (3H, t, J=7.1). MS (FAB) 442.2329(MH⁺, calcd. 442.2342).

Example 51 Preparation of4S-[(6-Methyl-naphthalene-2-carbonyl)-amino]-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoicAcid Ethyl Ester

[0221]

[0222] Compound 51 was prepared according to the method of Example 1,using as starting material 6-methyl-2-naphthoic acid. ¹H NMR (CDCl₃)δ8.42 (1H, s), 7.95 (1H, dd, J=8.6, 1.7), 7.84 (1H, d, J=8.4), 7.79 (1H,d, J=8.6), 7.63 (1H, s), 7.36 (1H, dd, J=8.6, 1.4), 6.97 (1H, dd,J=15.6, 5.3), 6.01 (1H, d, J=15.6), 5.99 (1H, s), 4.90-4.78 (1H, m),4.17 (2H, q, J=7.1), 3.43-3.30 (2H, m), 2.70-2.60 (2H, m), 2.52 (3H, s),2.20-2.05 (1H, m), 2.00-1.80 (2H, m), 1.26 (3H, t, J=1.7). MS (FAB)395.1964 (MH⁺, calcd. 395.1971), 417 (MNa⁺).

Example 52 Preparation of4S-[(6-Bromo-2H-chromene-3-carbonyl)-amino]-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoicAcid Ethyl Ester

[0223]

[0224] Compound 52 was prepared according to the method of Example 1,using as starting material 6-bromo-2H-chromene-3-carboxylic acid. ¹H NMR(CDCl₃) δ8.72 (1H, d, J=5.2), 7.28-7.23 (2H, m), 7.16 (1H, s), 6.86 (1H,dd, J=15.6, 5.6), 6.72 (1H, d, J=9.1), 5.96 (1H, dd, J=5.6, 1.4), 5.02(d, J=1.2), 4.60-4.49 (1H, m), 4.17 (2H, q, J=7.1), 3.43-3.36 (2H, m),2.59-2.40 (2H, m), 2.04-1.76 (3H, m), 1.27 (3H, t, J=7.1). MS (FAB)463.0883(MH⁺, calcd 463.0869), 485 (MNa⁺).

Example 53 Preparation of4S-[(7-Bromo-naphthalene-2-carbonyl)-amino]-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoicAcid Ethyl Ester

[0225]

[0226] Compound 53 was prepared according to the method of Example 1,using as starting material 7-bromo-2-naphthoic acid. ¹H NMR (CDCl₃)δ8.82 (1H, d, J=5.7), 8.39 (1H, s), 8.09 (1H, d, J=1.6), 8.02 (1H, dd,J=8.6, 1.6), 7.85 (1H, d, J=8.6), 7.73 (1H, d, J=8.7), 7.61 (1H, dd,J=8.7, 1.9), 6.96 (1H, dd, J=15.6, 5.4), 6.06 (1H, s), 6.03 (1H, d,J=15.6), 4.85-4.70 (1H, m), 4.17 (2H, q, J=7.1), 3.45-3.30 (2H, m),2.70-2.40 (2H, m), 2.20-1.80 (3H, m), 1.27 (3H, t, J=7.1). MS (FAB)459.0906 (MH⁺, calcd. 459.0919), 481 (MNa+).

Example 54 Preparation of4S-[(7-Hydroxy-naphthalene-2-carbonyl)-amino]-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoicAcid Ethyl Ester

[0227]

[0228] Compound 54 was prepared according to the method of Example 1,using as starting material 7-hydroxy-2-naphthoic acid. ¹H NMR (CDCl₃)δ8.35 (1H, d, J=6.9), 8.19 (1H, s), 7.74 (1H, d, J=9.7), 7.70 (1H, d,J=8.6), 7.64 (1H, d, J=8.8), 7.22 (1H, s), 7.15 (1H, d, J=8.8), 6.96(1H, dd, J=15.6, 5.3), 6.58 (1H, s), 6.03 (1H, d, J=15.6), 4.90-4.73(1H, m), 4.17 (2H, q, J=7.1), 3.40-3.20 (2H, m), 2.65-2.30 (2H, m),2.20-2.10 (1H, m), 1.90-1.70 (2H, m), 1.22 (3H, t, J=7.1). MS (FAB)397.1777 (MH⁺, calcd. 397.1763), 419 (MNa⁺).

Example 55 Preparation of5-(2-oxo-pyrrolidin-3S-yl)-4S-[3-(2-phenoxy-phenyl)-ureido]-pent-2-enoicAcid Ethyl Ester

[0229]

[0230] Compound 55 was prepared according to the method of Example 24,using 2-phenoxyphenyl isocyanate. ¹H NMR (CDCl₃) δ8.22 (1H, d, J=6.8),7.67 (1H, s), 7.48-7.38 (2H, m), 7.16-7.03 (2H, m), 7.03-6.94 (2H, m),6.94-6.78 (4H, m), 5.97 (1H, dd, J=15.7, 1.4), 5.46 (1H, s), 4.61-4.48(1H, m), 4.17 (2H, q, J=7.1), 3.28-3.12 (2H, m), 2.60-2.20 (2H, m),1.92-1.70 (2H, m), 1.65-1.50 (1H, m), 1.27 (3H, t, J=7.1). MS (FAB)412.2434 (MH⁺, calcd 412.2448), 434 (MNa⁺).

Example 56 Preparation of4S-(3-naphthalen-1-yl)-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoic AcidEthyl Ester

[0231]

[0232] Compound 56 was prepared according to the method of Example 24,using 1-naphthyl isocyanate. ¹H NMR (CDCl₃) δ8.05-7.97 (2H, m),7.84-7.82 (2H, m), 7.63 (1H, d, J=8.2), 7.59-7.40 (4H, m), 6.88 (1H, dd,J=15.7, 5.1), 5.98 (1H, dd, J=15.7, 1.5), 5.82 (1H, S), 4.70-4.60 (1H,m), 4.17 (2H, q, J=7.1), 3.35-3.28 (2H, m), 2.60-2.40 (2H, m), 2.00-1.75(2H, m), 1.68-1.56 (1H, m), 1.27 (3H, t, J=7.1). MS (FAB) 396.1912 (MH⁺,calcd. 396.1923), 418 (MNa⁺).

E7xample 57 Preparation of4S-[3-(3,5-dimethoxy-phenyl)ureido]-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoicAcid Ethyl Ester

[0233]

[0234] Compound 57 was prepared according to the method of Example 24,using 3,5-dimethoxyphenyl isocyanate. ¹H NMR (CDCl₃) 6.89 (1H, dd,J=15.6, 5.0), 6.64 (2H, s), 6.14 (1H, s), 6.0 (1H, dd, J=15.6, 1.5),5.86 (1H, s), 4.62-4.51 (1H, m), 4.17 (2H, q, J=7.1), 3.8 (6H, s),3.43-3.34 (2H, m), 2.63-2.43 (2H, m), 2.00-1.80 (2H, m), 1.75-1.63 (1H,m), 1.28 (3H, t, J=7.1). MS (FAB) 406.1964 (MH⁺, calcd. 406.1978), 428(MNa⁺).

Example 58 Preparation of4S-[3-(3,5-dimethyl-phenyl)-ureido]-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoicAcid Ethyl Ester

[0235]

[0236] Compound 58 was prepared according to the method of Example 24,using 3,5-dimethylphenyl isocyanate. ¹H NMR (CDCl₃) δ6.99 (2H, s), 6.88(1H, dd, J=15.6, 5.1), 6.65 (1H, s), 5.98 (1H, dd, J=15.7, 1.4), 5.89(1H, s), 4.61-4.52 (1H, m), 4.17 (2H, q, J=7.1), 3.40-3.32 (2H, m),2.63-2.42 (2H, m), 2.25 (6H, s), 1.99-1.80 (2H, m), 1.71-1.60 (1H, m),1.27 (3H, t, J=7.1). MS (FAB) 374.2072 (MH⁺, calcd.374.2080), 396(MNa⁺).

Example 59 Preparation of6-carbamoyl-4S-[3-(1-ethoxycarbonyl-3-methylbutyl)-ureido]-hex-2-enoicAcid Ethyl Ester

[0237]

[0238] The functionalized resin prepared in Example 25(a) (100 mg, 0.059mmol) in DMF (5 mL) was treated with ethyl-2-isocyanato-4-methylvalerate (3 eq, 0.18 mmol, 33 mg), and agitated for 2 h. The resin waswashed with CH₂Cl₂ (3×10 mL), then suspended in a 95:5 TFA- CH₂Cl₂solution (10 mL) for 1 h, with vigorous stirring. The resin was removedby filtration, and the filtrate was evaporated. The resulting oil waspurified by silica gel chromatography to yield 16.1 mg (73%) of product59. ¹H NMR (CDCl₃) δ6.87 (1H, dd, J=15.8, 4.8), 5.94 (1H, d, J=16.5),4.54-4.38 (1H, m), 4.25-4.14 (1H, m), 4.22-4.10 (4H, m), 2.40-1.40 (7H,m), 1.28 (6H, t, J=7.4), 0.95 (6H, d, J=6.3). MS (FAB) 386 (MH⁺), 408(MNa⁺).

Example 60 Preparation of4S-[2-(3-methoxy-phenoxy)-acetylamino]-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoicAcid Ethyl Ester

[0239]

[0240] Compound 60 was prepared according to the method of Example 1,using 3-methoxyphenoxyacetic acid. ¹H NMR (CDCl₃) δ7.30 (1H, d, J=8.4),7.22 (1H, t, J=8.5), 6.87 (1H, dd, J=15.7, 5.7), 6.60-6.52 (3H, m), 5.90(1H, d, J=15.7), 5.70 (1H, s), 4.79-4.73 (1H, m), 4.53 (2H, ABq,J=15.0), 4.19 (2H, q, J=7.1), 3.79 (3H, s), 3.35-3.30 (2H, m), 2.44-2.33(2H, m), 2.16-2.06 (1H, m), 1.86-1.65 (2H, m), 1.28 (3H, t, J=7.1). MS(FAB) 391.1865 (MH⁺, calcd 391.1869), 413 (MNa⁺).

Example 61 Preparation of4S-[2-(3-chloro-phenoxy)-acetylamino]-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoicAcid Ethyl Ester

[0241]

[0242] Compound 61 was prepared according to the method of Example 1,using 3-chlorophenoxyacetic acid. ¹H NMR (CDCl₃) δ7.63 (1H, d, J=7.7),7.25 (1H, t, J=8.1), 7.03-6.82 (4H, m), 5.94 (1H, d, J=15.6), 5.77 (1H,s), 4.75-4.72 (1H, m), 4.52 (2H, ABq, J=14.8), 4.19 (2H, q, J=7.1),3.35-3.30 (2H, m), 2.44-2.32 (2H, m), 2.12-2.02 (1H, m), 1.87-1.65 (2H,m), 1.28 (3H, t, J=7.1). MS (ES) 371 (MH⁺).

Example 62 Preparation of4S-[2-(3,4-dichloro-phenoxy)-acetylamino]-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoicAcid Ethyl Ester

[0243]

[0244] Compound 62 was prepared according to the method of Example 1,using 3,4-dichlorophenoxyacetic acid. ¹H NMR (CDCl₃) δ7.84 (1H, d,J=7.2), 7.37 (1H, d, J=8.8), 7.10 (1H, s), 6.86 (1H, d, J=9.2), 6.84(1H, dd, J=15.6, 5.9), 5.90 (1H, d, J=17.1), 5.64 (1H, s), 4.72-4.65(1H, m), 4.51 (2H, ABq, J=14.7), 4.19 (2H, q, J=7.1), 3.36-3.31 (2H, m),2.44-2.32 (2H, m), 2.10-1.69 (3H, m), 1.30 (3H, t, J=7.1). MS (FAB)429.0971 (MH⁺, calcd 429.0984).

Example 63 Preparation of4S-[2-(3-chloro-phenyl)-acetylamino]-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoicAcid Ethyl Ester

[0245]

[0246] Compound 63 was prepared according to the method of Example 1,using 3-chlorophenylacetic acid. ¹H NMR (CDCl₃) δ7.44 (1H, d, J=7.01),7.30-7.15 (4H, m), 6.80 (1H, d, J=15.7, 5.4), 6.00 (1H, s), 5.84 (1H,dd, J=15.6, 1.5), 4.61-4.50 (1H, m), 4.17 (2H, q, J=7.1), 3.52 (2H, s),3.38-3.28 (2H, m), 2.42-2.28 (2H, m), 2.00-1.70 (2H, m), 1.70-1.60 (1H,m), 1.27 (3H, t, J=7.1). MS (FAB) 379.1419 (MH⁺, calcd. 379.1425), 401(MNa⁺).

Example 64 Preparation of 4S-[3-(2,5-dibromo-phenyl)-acryloylamino]-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoic Acid Ethyl Ester

[0247]

[0248] Compound 64 was prepared according to the method of Example 1,using 2,5-dibromocinnamic acid. ¹H NMR (CDCl₃) δ8.15 (1H, d, J=6.4),7.92 (1H, d, J=15.6), 7.71 (1H, s), 7.47 (1H, d, J=8.6), 7.32 (1H, d,J=8.6), 6.93 (1H, dd, J=15.6, 5.4), 6.43 (1H, d, J=15.6), 6.03 (1H, d;J=15.6), 5.62 (1H, s), 4.68-4.63 (1H, m), 4.22 (2H, d, J=7.1), 3.42-3.37(2H, m), 2.54-2.44 (1H, m), 2.05-1.58 (4H, m), 1.30 (3H, t, J=7.1). MS(FAB) 515.0021 (MH⁺, calcd. 515.0005).

Example 65 Preparation of 4S-[(6-hydroxy-naphthalene-2-carbonyl)-amino]-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoic Acid EthylEster

[0249]

[0250] Compound 65 was prepared according to the method of Example 1,using 6-hydroxy-2-naphthoic acid. ¹H NMR (CD₃OD) δ8.34 (1H, s), 7.86(2H, d, J,=8.9), 7.73 (1H, d, J=8.7), 7.16 (1H, s), 7.15 (1H, t, J=6.4),7.05 (1H, dd, J=15.7, 5,5), 6.04 (1H, d, J=15.7), 4.22 (2H, d, J=7.2),3.36-3.29 (2H, m), 2.58-2.54 (1H, m), 2.54-2.42 (1H, m), 2.24-2.14 (1H,m), 1.95-1.88 (1H, m), 1.80-1.75 (1H, m), 1.27 (3H, t, J=7.0). MS (FAB)397.1775 (MH⁺, calcd. 397.1763).

Example 66 Preparation of4S-[(6-bromo-7-methyl-2H-chromene-3-carbonyl)amino]-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoicAcid Ethyl Ester

[0251]

[0252] Compound 66 was prepared according to the method of Example 1,using 6-bromo-7-methyl-2H-chromen-3-carboxylic acid. ¹H NMR (CDCl₃) δ835 (1H, d, J=7.1), 7.20 (1H, s), 7.10 (1H, s), 6.79 (1H, dd, J=15.7,5.5), 6.66 (1H, s), 5.86 (1H, dd, J=15.7, 1.5), 4.89 (2H, d, J=1.3),4.65-4.51 (1H, m), 4.10 (2H, q, J=7.1); 3.35-3.25 (2H, m), 2.50-2.28(2H, m), 2.25 (3H, s), 2.02-1.87 (1H, m), 1.83-1.70 (1H, m), 1.65-1.55(1H, m), 1.19 (3H, t, J=7.2). MS (FAB) 477.1043 (MH⁺, calcd. 477.1025).

Example 67 Preparation of 4S-[(2H-chromene-3-carbonyl)- amino]-5-(2-oxopyrrolidin-3S-yl)-pent-2-enoic Acid Ethyl Ester -

[0253]

[0254] Compound 67 was prepared according to the method of Example 1,using 2H-chromene-3-carboxylic acid. ¹H NMR (CDCl₃) δ8.46 (1H, d,J=5.4), 7.23-7.12 (3H, m), 6.94-6.81 (3H, m), 5.97 (1H, dd, J=15.6,1.4), 5.62 (1H, s), 5.03 (1H, d, J=1.2), 4.64-4.53 (1H, m), 4.17 (2H, q,J=7.2), 3.42-3.38 (2H, m), 2.58-2.40 (2H, m),2.03-1.75 (3H, m),1.27 (3H,t, J=7.2) MS (FAB) 385.1774 (MH⁺, calcd. 385.1763).

Example 68 Preparation of4S-[(4-bromo-6-methyl-naphthalene-2-carbonyl)amino]-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoicAcid Ethyl Ester

[0255]

[0256] Compound 68 was prepared according to the method of Example 1,using 4-bromo-6-methyl-2-naphthoic acid. ¹H NMR (CDCl₃) δ8.78 (1H, s),8.69 (1H, s), 8.02 (1H, d, J=8.3), 7.80 (1H, d, J=8.4), 7.68 (1H, s),7.59 (1H, s), 7.01 (1H, dd, J=15.5, 4.3), 6.08 (1H, d, J=15.5), 5.91(1H, s), 4.81 (1H, s), 4.21 (2H, q, J=7.1), 3.49 (2H, d, J=8.8),2.63-2.54 (2H, m), 2.50 (31rl, s), 2.17-1.84 (2H, m), 1.24 (3H, t,J=7.0). MS (FAB) 473.1068 (MH⁺, calcd. 473.1076)

Example 69 Preparation of4S-[(3-amino-naphthalene-2-carbonyl)-amino]-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoicAcid Ethyl Ester

[0257]

[0258] Compound 69 was prepared according to the method of Example 1,using 3-amino-2-naphthoic acid. ¹H NMR (CDCl₃) δ9.31 (brs 1H), 9.08(brs, 1H), 8.39 (s, IH), 8.23 (s, 1H), 7.88-7.24 (m, 4H), 7.15 (brs 1H),7.02 (dd, 1H, J=15.7, 5.4) 1. 6.12 (d, 1H, J=15.5), 5.86 (brs 1H),4.74-4.70 (m, 1H), 4.20 (q, 2H, J=7.1),_(—)3.31-3.28 (m, 2H), 2.62-1.64(m, 5H), 1.30 (t, 3H, J=7.1), MS (FAB) 396.1913 (MH⁺, calcd. 396.1923).

BIOCHEMICAL AND BIOLOGICAL EVALUATION

[0259] Results of biochemical and biological tests conducted usingvarious compounds of the invention are described below.

[0260] Inhibition of Rhinovirus 3C Protease Activity

[0261] Stock solutions (50 mM, in DMSO) of various compounds wereprepared; dilutions were in the same solvent. Recombinant rhinovirus 3Cproteases (see Birch et al., “Purification of recombinant humanrhinovirus 14 3C protease expressed in Escherichia coli,” Protein Expr.Pur. 1995, 6(5), 609-618) from serotypes 14, 16, and 2 were prepared bythe following standard chromatographic procedures: (1) ion exchangeusing Q Sepharose Fast Flow from Pharmacia; (2) affinity chromatographyusing Affi-Gel Blue from Biorad; and (3) sizing using Sephadex G-100from Pharmacia. Each assay sample contained 2% DMSO, 50 mM tris pH 7.6,1 mM EDTA, a test compound at the indicated concentration, approximately1 μM substrate, and 50-100 nM protease. The k_(obs/I) values wereobtained from reactions initiated by addition of enzyme rather thansubstrate. RVP activity was measured in the fluorescence resonanceenergy transfer assay. The substrate was (N-terminal)DABCYL-(Gly-Arg-Ala-Val-Phe-Gln-Gly-Pro-Val-Gly)-EDANS. In the uncleavedpeptide, the EDANS fluorescence was quenched by the proximal DABCYLgroup. When the peptide was cleaved, the quenching was relieved, andactivity was measured as an increase in fluorescence signal. Data wereanalyzed using standard non-linear fitting programs (Enzfit), and areshown in the Table below. In the Table, unless otherwise indicated, alldata are for rhinovirus 3C protease from HRV serotype-14 (produced fromthe infectious cDNA clone constructed by Dr. Robert Rueckert, Institutefor Molecular Virology, University of Wisconsin, Madison, Wis.). Thedata in the column designated k_(obs)/[I] were measured from progresscurves in enzyme start experiments.

[0262] Antirhinoviral H1-HeLa Cell Culture Assay

[0263] In this cell protection assay, the ability of compounds toprotect cells against HRV infection was measured by the XTT dyereduction method, which is described in Weislow et al., J. Natl. CancerInst. 1989, vol. 81, 577-586.

[0264] H1-HeLa cells were infected with HRV-14 at a multiplicity ofinfection (m.o.i.) of 0.13 (virus particles/cell) or mock-infected withmedium only. Infected or mock-infected cells were resuspended at 8×10⁵cells per mL, and incubated with appropriate concentrations of thecompounds to be tested. Two days later, XTT/PMS was added to test platesand the amount of formazan produced was quantifiedspectrophotometrically at 450/650 nm. The EC₅₀ value was calculated asthe concentration of compound that increased the percentage of formazanproduction in compound-treated, virus-infected cells to 50% of thatproduced by compound-free, mock-infected cells. The 50% cytotoxic dose(CC₅₀) was calculated as the concentration of compound that decreasedthe percentage of formazan produced in compound-treated, mock-infectedcells to 50% of that produced by compound-free, mock-infected cells.

[0265] All strains of human rhinovirus (HRV) for use in this assay werepurchased from American Type Culture Collection (ATCC), except for HRVserotype-14 (produced from the infectious cDNA clone constructed by Dr.Robert Rueckert, Institute for Molecular Virology, University ofWisconsin, Madison, Wis.). HRV stocks were propagated and viral assayswere performed in H1-HeLa cells (ATCC). Cells were grown in minimalessential medium with 10% fetal bovine serum, available from LifeTechnologies (Gaithersburg, Md.).

[0266] The compounds were tested against control compounds WIN 51711,WIN 52084, and WIN 54954 (obtained from Sterling-WinthropPharmaceuticals), Pirodavir (obtained from Janssen Pharmaceuticals), andPleconaril (prepared according to the method described in Diana et al.,J. Med. Chem 1995, vol. 38, 1355). Antiviral data obtained for the testcompounds are shown in the Table, where all data are for HRV serotype-14unless otherwise noted in parentheses. The designation “ND” indicatesthat a value was not determined for that compound. Protease Inhibitionand Antiviral Activity of Formula I Compounds Protease InhibitionCompound k_(obs)/I Cell Protection Toxicity No. (M⁻¹sec⁻¹) EC₅₀ (μM)CC₅₀ (μM)  1 1090 (HRV-14) 0.15 >100 110 (HRV-2) 1.35  2 400 — —  3 25601.4 >10  4 258 — —  5 173 — —  6 79 — —  7 36 — —  8 980 2.67 >10  91958 1.81 >10 10 55 — — 11 750 — — 12 990 2.77 >10 13 169 — — 14 219 — —15 2021 1.53 >10 16 664 — — 17 315 — — 18 262 — — 19 1230 1.36 >10 201369 4.39 >10 21 1317 3.07 17.78 22 581, 673 — — 23 4080 1.29 >10 241050 4.6 >10 25 150 0.6 >100 22 (HRV-1A) 35 (HRV-10) 26 95 1.5 >100 59(HRV-1A) 12.4 (HRV-10) 27 45 3.9 >100 28 64 14.1 >100 29 62 31.6 >100 30345 3.2 >100 31 110 7.1 >100 32 83 1.8 >100 33 27 12.6 >100 3410 >100 >100 35 35 >100 100 36 10 >100 >100 37 6 >100 >100 38 711.0 >100 39 615 — — 40 1270 — — 41 2190 2.36 >100 42 272 — — 43 34582.14 >100 44 19700 (HRV-14)  .16 (HRV-14) >100  800 (HRV-89)  5.1(HRV-1A)  2200 (HRV-16) 0.459 (HRV-10)  385 (HRV-2) .645 (HRV-2) 45 47451.94 >100 46 1830 — — 47 283 — — 48 2857 0.625 >100 49 14400 2.512(HRV-1A) >100 0.316 (HRV-10)  0.49 (HRV-14) 50 225 — — 51 50200.880 >100 52 25000 5.065 (HRV-1A) 65 372 (HRV-2) 0.546 (HRV-10) 0.175(HRV-14) 53 31400 4.180 (HRV-1A) 56.2 385 (HRV-2) 0.546 (HRV-10) 0.184(HRV-14) 0.422 (HRV-2)  54 220 — — 35 (HRV-2) 55 200 — — 56 117 >10 >1057 388 >10 >10 58 185 — — 59 400 19.6 >100 60 77 — — 61 103 — — 62 1346.1 >10 63 7 — — 64 6850 65 570 66 25000 67 886 1.191 >100 68 266013.03 >100 69 142 WIN 51711 — 0.78 >60 WIN 52084 — 0.07 >10 WIN 54954 —2.13 >63 Pirodavir — 0.03 >10 Pleconaril — 0.01 >10

[0267] While the invention has been described in terms of preferredembodiments and specific examples, those skilled in the art willrecognize through routine experimentation that various changes andmodifications can be made without departing from the spirit and scope ofthe invention. Thus, the invention should be understood as not beinglimited by the foregoing detailed description, but as being defined bythe appended claims and their equivalents.

What is claimed is:
 1. A compound of formula:

wherein: R^(a1) is a cycloalkyl, heterocycloalkyl, aryl or heteroarylgroup, provided that R^(a1) is not a substituted pyrrolidinyl, where thecycloalkyl, heterocycloalkyl, aryl or heteroaryl group is unsubstitutedor substituted with one or more suitable substituents; R^(c) is asubstituent having the formula:

wherein: R^(f) and R^(g) are each independently H or lower alkyl; m is 0or 1; p is an integer of from 0 to 5; A₁ is CH or N; when p is 1, 2, 3,4, or 5, A₂ is C(R^(h))(R^(i)), N(R^(j)), S, S(O), S(O)₂, or O, and whenp is 0, A₂ is C(R^(h))(R^(i))(R^(j)), N(R^(i))(R^(j)), S(R^(i)),S(O)(R^(i)), S(O)₂(R^(i)), or O(R^(i)), where each R^(h), R^(i) andR^(J) is independently H or a lower alkyl group; each A₃ present isindependently C(R^(h))(R^(i)), N(R^(j)), S, S(O), S(O)₂, or O; whereeach R^(h), R^(i) and R^(j) is independently H or lower alkyl; when p is1, 2, 3, 4, or 5, A₄ is N(R^(k)), C(R^(h))(R^(i)), or O; and when p is0, A₄ is N(R^(k))(R^(l)), C(R^(h))(R^(i))(R^(j)), and O(R^(l)), whereeach R^(h), R^(i) and R^(j) is independently H or lower alkyl, eachR^(k) is H, alkyl, aryl, or acyl, and each R¹ is H, alkyl, or aryl;provided that no more than two heteroatoms occur consecutively in theabove-depicted ring formed by A₁, (A₂)_(m), (A₃)_(p), A₄, and C═O, whereeach dotted line in the ring depicts a single bond when A₂ is presentand a hydrogen atom when A₂ is absent; R^(d) is H, halogen, hydroxyl oran alkyl, alkoxy or alkylthio group, where the alkyl, alkoxy oralkylthio group is unsubstituted or substituted with one or moresuitable substituents; R^(b) is H or an alkyl group, unsubstituted orsubstituted with one or more suitable substituents; Z and Z¹ are eachindependently H, F, an alkyl, cycloalkyl, heterocycloalkyl, aryl orheteroaryl group, where the alkyl, cycloalkyl, heterocycloalkyl, aryl orheteroaryl group is unsubstituted or substituted with one or moresuitable substituents, —C(O)R^(n) —CO₂R^(n) —CN, —C(O)NR^(n)R^(o),—C(O)NR^(n)OR^(o), —C(S)R^(n), —C(S)OR^(n) —C(S)NR^(n)R^(o),—C(═NR^(n))R^(o), —C(═NR^(n))OR^(o), —NO₂, —SOR^(o), —SO₂R^(n),—SO₂NR^(n)R^(o), —SO₂(NR^(n))(OR^(o)), —SONR^(n), —SO₃R^(n),—PO(OR^(n))₂, —PO(OR^(n))(OR^(o)), —PO(NR^(n)R^(o))(OR^(p)),—PO(NR^(n)R^(o))(NR^(p)R^(q)), —C(O)NR^(n)NR^(o)R^(p),—C(S)NR^(n)NR^(o)R^(p), where R^(n), R^(o), R^(p) and R^(q) are eachindependently H or an alkyl, cycloalkyl, aryl, heterocycloalkyl, acyl orthioacyl group, where the alkyl, cycloalkyl, aryl, heterocycloalkyl,acyl or thioacyl group is unsubstituted or substituted with one or moresuitable substituents, or where any two of the R^(n), R^(o), R^(p) andR^(q), taken together with the atoms to which they are bonded, form aheterocycloalkyl group, which may be optionally substituted, or Z andR^(d), together with the atoms to which they are bonded, form acycloalkyl or heterocycloalkyl group, where Z and R^(d) are as definedabove except for moieties that cannot form the cycloalkyl orheterocycloalkyl group, or Z and Z¹, together with the atoms to whichthey are bonded, form a cycloalkyl or heterocycloalkyl group, where Zand Z¹ are as defined above (except for moieties that cannot form thecycloalkyl or heterocycloalkyl group); or a prodrug, pharmaceuticallyacceptable salt, pharmaceutically active metabolite, or pharmaceuticallyacceptable solvate thereof.
 2. A compound, prodrug, pharmaceuticallyacceptable salt, pharmaceutically active metabolite, or pharmaceuticallyacceptable solvate according to claim 1 having the formula:

wherein R^(a1) is as defined in claim 1; and R^(c) is


3. A compound, prodrug, pharmaceutically acceptable salt,pharmaceutically active metabolite, or pharmaceutically acceptablesolvate according to claims 1 or 2, wherein R^(a1) is a(C₃-C₈)cycloalkyl, heterocycloalkyl, aryl or heteroaryl group, whereinthe (C₃-C₈)cycloalkyl, heterocycloalkyl, aryl or heteroaryl group isunsubstituted or substituted with one or more substituents independentlyselected from (C₁-C₄)alkyl, aryl(C₁-C₄)alkyl, aryl, (C₃-C₈)cycloalkyl,heterocycloalkyl, heteroaryl, halo, hydroxyl, nitro, amino,(C₁-C₄)alkylamino, di-(C₁-C₄)alkylamino, aryl(C₁-C₄)alkoxy,aryloxy(C₁-C₄)alkyl, alkylenedioxy, aryloxy, (C₃-C₈)cycloalkoxy,heteroaryloxy, (C₁-C₄)haloalkyl, (C₁-C₄)alkoxy, (C₁-C₄)haloalkoxy,hydroxamino, (C₁-C₄)alkoxycarbonyl, (C₁-C₄)alkylcarbonylamino,(C₁-C₄)alkylcarbonyl, mercapto, alkylthio or arylthio, where the(C₁-C₄)alkyl and (C₃-C₈)cycloalkyl moieties thereof are optionallysubstituted by one or more of (C₁-C₄)alkyl (except for alkyl), halo,(C₁-C₄)haloalkyl, (C₁-C₄)alkoxy, (C₁-C₄)haloalkoxy and theheterocycloalkyl, aryl or heteroaryl moieties thereof are unsubstitutedor are optionally substituted by one or more substituents independentlyselected from alkyl, haloalkyl, alkylenedioxy, nitro, amino,hydroxamino, alkylamino, dialkylamino, halo, hydroxyl, alkoxy,haloalkoxy, aryloxy, mercapto, alkylthio or arylthio groups.
 4. Acompound, prodrug, pharmaceutically acceptable salt, pharmaceuticallyactive metabolite, or pharmaceutically acceptable solvate according toclaims 1 or 2, wherein R^(a1) is a pyrazolyl, indolyl, chromenyl,benzofuranyl, benzothienyl, benzimidazolyl, triazolyl, quinolyl,thiazolidinyl, quinoxalinyl, phenyl or naphthyl group, where thepyrazolyl, indolyl, chromenyl, benzofuranyl, benzothienyl,benzimidazolyl, triazolyl, quinolyl, thiazolidinyl, quinoxalinyl, phenylor naphthyl group is unsubstituted or substituted with one or moresubstituents independently selected from (C₁-C₄)alkyl, aryl(C₁-C₄)alkyl,aryl, halo, hydroxyl, nitro, amino, (C₁-C₄)alkylamino,di-(C₁-C₄)alkylamino, (C₁-C₄)alkoxy, aryl(C₁-C₄)alkoxy,aryloxy(C₁-C₄)alkyl, methylenedioxy, aryloxy, (C₁-C₄)haloalkyl,(C₁-C₄)haloalkoxy, (C₁-C₄)alkoxycarbonyl, (C₁-C₄)alkylcarbonylamino, or(C₁-C₄)alkylcarbonyl, where the (C₁-C₄)alkyl moieties thereof areoptionally substituted by one or more of halo, (C₁-C₄)alkoxy or(C₁-C₄)haloalkoxy and the aryl moieties thereof are unsubstituted or areoptionally substituted by one or more substituents independentlyselected from alkyl, haloalkyl, alkylenedioxy, nitro, amino, alkylamino,dialkylamino, halo, hydroxyl, alkoxy, haloalkoxy or aryloxy groups.
 5. Acompound, prodrug, pharmaceutically acceptable salt, pharmaceuticallyactive metabolite, or pharmaceutically acceptable solvate according toclaims 1 or 2, wherein R^(a1) is a is a pyrazolyl, indolyl,N-methylindolyl, chromenyl, benzofuranyl, benzothienyl, benzimidazolyl,, N-methylbenzimidazolyl, triazolyl, quinolyl, thiazolidinyl,quinoxalinyl, phenyl or naphthyl group, where the pyrazolyl, indolyl,chromenyl, benzofuranyl, benzothienyl, benzimidazolyl, triazolyl,quinolyl, thiazolidinyl, quinoxalinyl, phenyl or naphthyl group isunsubstituted or substituted with one or more substituents independentlyselected from methyl, ethyl, benzyl, phenethyl, phenyl, naphthyl, halo,hydroxyl, nitro, amino, methylamino, di-methylamino, methoxy, benzyloxy,methylenedioxy, (C₁-C₄)haloalkyl, (C₁-C₄)haloalkoxy, methoxycarbonyl,methylcarbonylamino, benzoyloxymethylene (phenylcarbonyloxymethyl-)ormethylcarbonyl.
 6. A compound of formula:

wherein: R^(a2) is an alkyl, aryl or heteroaryl group, where the alkyl,aryl or heteroaryl group is unsubstituted or substituted with one ormore suitable substituents; and R^(c) is a substituent having theformula:

wherein: R^(f) and R^(g) are each independently H or lower alkyl; m is 0or 1; p is an integer of from 0 to 5; A₁ is CH or N; when p is 1, 2, 3,4, or 5, A₂ is C(R^(h))(R^(i)), N(R^(j)), S, S(O), S(O)₂, or O, and whenp is 0, A₂ is C(R^(h))(R^(i))(R^(j)), N(R^(i))(R^(j)), S(R^(i)),S(O)(R^(i)), S(O)₂(R^(i)), or O(R^(i)), where each R^(h), R^(i) andR^(j) is independently H or a lower alkyl group; each A₃ present isindependently C(R^(h))(R^(i)), N(R^(j)), S, S(O), S(O)₂, or O; whereeach R^(h), R^(i) and R^(j) is independently H or lower alkyl; when p is1, 2, 3, 4, or 5, A₄ is N(R^(k)), C(R^(h))(R^(i)), or O; and when p is0, A₄ is N(R^(k))(R^(l)), C(R^(h))(R^(i))(R^(j)), and O(R^(l)), whereeach R^(h), R^(i) and R^(j) is independently H or lower alkyl, eachR^(k) is H, alkyl, aryl, or acyl, and each R^(l) is H, alkyl, or aryl;provided that no more than two heteroatoms occur consecutively in theabove-depicted ring formed by A₁, (A₂)_(m), (A₃)_(p), A₄, and C═O, whereeach dotted line in the ring depicts a single bond when A₂ is presentand a hydrogen atom when A₂ is absent; R^(d) is H, halogen, hydroxyl oran alkyl, alkoxy or alkylthio group, where the alkyl, alkoxy oralkylthio group is unsubstituted or substituted with one or moresuitable substituents; R^(b) is H or an alkyl group, unsubstituted orsubstituted with one or more suitable substituents; Z and Z¹ are eachindependently H, F, an alkyl, cycloalkyl, heterocycloalkyl, aryl orheteroaryl group, where the alkyl, cycloalkyl, heterocycloalkyl, aryl orheteroaryl group is unsubstituted or substituted with one or moresuitable substituents, —C(O)R^(n) —CO₂R^(n) —CN, —C(O)NR^(n)R^(o),—C(O)NR^(n)OR^(o), —C(S)R^(n), —C(S)OR^(n) —C(S)NR^(n)R^(o),—C(═NR^(n))R^(o), —C(═NR^(n))OR^(o), —NO₂, —SOR^(o), —SO₂R^(n),—SO₂NR^(n)R^(o), —SO₂(NR^(n))(OR^(o)), —SONR^(n), —SO₃R^(n),—PO(OR^(n))₂, —PO(OR^(n))(OR^(o)), —PO(NR^(n)R^(o))(OR^(p)),—PO(NR^(n)R^(o))(NR^(p)R^(q)), —C(O)NR^(n)NR^(o)R^(p),—C(S)NR^(n)NR^(o)R^(p), where R^(n), R^(o), R^(p) and R^(q) are eachindependently H or an alkyl, cycloalkyl, aryl, heterocycloalkyl, acyl orthioacyl group, where the alkyl, cycloalkyl, aryl, heterocycloalkyl,acyl or thioacyl group is unsubstituted or substituted with one or moresuitable substituents, or where any two of the R^(n), R^(o), R^(p) andR^(q), taken together with the atoms to which they are bonded, form aheterocycloalkyl group, which may be optionally substituted, or Z andR^(d), together with the atoms to which they are bonded, form acycloalkyl or heterocycloalkyl group, where Z and R^(d) are as definedabove except for moieties that cannot form the cycloalkyl orheterocycloalkyl group, or Z and Z¹, together with the atoms to whichthey are bonded, form a cycloalkyl or heterocycloalkyl group, where Zand Z¹ are as defined above (except for moieties that cannot form thecycloalkyl or heterocycloalkyl group); or a prodrug, pharmaceuticallyacceptable salt, pharmaceutically active metabolite, or pharmaceuticallyacceptable solvate thereof.
 7. A compound, prodrug, pharmaceuticallyacceptable salt, pharmaceutically active metabolite, or pharmaceuticallyacceptable solvate according to claim 6, having the formula:

wherein: R^(a2) and R^(c) are as defined in claim
 6. 8. A compound,prodrug, pharmaceutically acceptable salt, pharmaceutically activemetabolite, or pharmaceutically acceptable solvate according to claims 6or 7, wherein R^(a2) is a (C₁-C₄)alkyl, aryl or heteroaryl group,wherein the (C₁-C₄)alkyl, (C₃-C₈)cycloalkyl, heterocycloalkyl, aryl andheteroaryl group is unsubstituted or substituted with one or moresuitable substituents.
 9. A compound, prodrug, pharmaceuticallyacceptable salt, pharmaceutically active metabolite, or pharmaceuticallyacceptable solvate according to claims 6 or 7, wherein R^(a2) is a(C₁-C₄)alkyl, phenyl or naphthyl group, where the (C₁-C₄)alkyl group isunsubstituted or substituted with one or more substituents independentlyselected from halo, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, C₁-C₄alkoxycarbonyl, and the phenyl or naphthyl group is unsubstituted orsubstituted with one or more substituents independently selected fromhalo, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy,methylenedioxy and phenoxy.
 10. A compound, prodrug, pharmaceuticallyacceptable salt, pharmaceutically active metabolite, or pharmaceuticallyacceptable solvate according to claims 6 or 7, wherein R^(a2) is anaphthyl, phenoxyphenyl, 3,5,-dimethoxyphenyl, 3,5-dimethylphenyl or anethoxycarbonyl-substituted branched (C₁-C₆) alkyl moiety.
 11. A compoundof formula:

wherein: R^(a3) is an aryl, heterocycloalkyl, heteroaryl orarylaminocarbonyl group, where the aryl, heterocycloalkyl, heteroaryl orarylaminocarbonyl group is unsubstituted or substituted with one or moresuitable substituents; and R^(c) is a substituent having the formula:

wherein: R^(f) and R^(g) are each independently H or lower alkyl; m is 0or 1; p is an integer of from 0 to 5; A₁ is CH or N; when p is 1, 2, 3,4, or 5, A₂ is C(R^(h))(R^(i)), N(R^(j)), S, S(O), S(O)₂, or O, and whenp is 0, A₂ is C(R^(h))(R^(i))(R^(j)), N(R^(i))(R^(j)), S(R^(i)),S(O)(R^(i)), S(O)₂(R^(i)), or O(R^(i)), where each R^(h), R^(i) andR^(j) is independently H or a lower alkyl group; each A₃ present isindependently C(R^(h))(R^(i)), N(R^(j)), S, S(O), S(O)₂, or O; whereeach R^(h), R^(i) and R^(j) is independently H or lower alkyl; when p is1, 2, 3, 4, or 5, A₄ is N(R^(k)), C(R^(h))(R^(i)), or O; and when p is0, A₄ is N(R^(k))(R^(l)), C(R^(h))(R^(i))(R^(j)), and O(R^(l)), whereeach R^(h), R^(i) and R^(j) is independently H or lower alkyl, eachR^(k) is H, alkyl, aryl, or acyl, and each R^(l) is H, alkyl, or aryl;provided that no more than two heteroatoms occur consecutively in theabove-depicted ring formed by A₁, (A₂)_(m), (A₃)_(p), A₄, and C═O, whereeach dotted line in the ring depicts a single bond when A₂ is presentand a hydrogen atom when A₂ is absent; R^(d) is H, halogen, hydroxyl oran alkyl, alkoxy or alkylthio group, where the alkyl, alkoxy oralkylthio group is unsubstituted or substituted with one or moresuitable substituents; R^(b) is H or an alkyl group, unsubstituted orsubstituted with one or more suitable substituents; R^(e) is H, halogen,hydroxyl or an alkyl, alkoxy or alkylthio group, where the alkyl, alkoxyor alkylthio group is unsubstituted or substituted with one or moresuitable substituents; Z and Z¹ are each independently H, F, an alkyl,cycloalkyl, heterocycloalkyl, aryl or heteroaryl group, where the alkyl,cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is unsubstitutedor substituted with one or more suitable substituents, —C(O)R^(n)—CO₂R^(n) —CN, —C(O)NR^(n)R^(o), —C(O)NR^(n)OR^(o), —C(S)R^(n),—C(S)OR^(n) —C(S)NR^(n)R^(o), —C(═NR^(n))R^(o), —C(═NR^(n))OR^(o), —NO₂,—SOR^(o), —SO₂R^(n), —SO₂NR^(n)R^(o), —SO₂(NR^(n))(OR^(o)), —SONR^(n),—SO₃R^(n), —PO(OR^(n))₂, —PO(OR^(n))(OR^(o)), —PO(NR^(n)R^(o))(OR^(p)),PO(NR^(n)R^(o))(NR^(p)R^(q)) —C(O)NR^(n)NR^(o)R^(p),—C(S)NR^(n)NR^(o)R^(p), where R^(n), R^(o), R^(p) and R^(q) are eachindependently H or an alkyl, cycloalkyl, aryl, heterocycloalkyl, acyl orthioacyl group, where the alkyl, cycloalkyl, aryl, heterocycloalkyl,acyl or thioacyl group is unsubstituted or substituted with one or moresuitable substituents, or where any two of the R^(n), R^(o), R^(p) andR^(q), taken together with the atoms to which they are bonded, form aheterocycloalkyl group, which may be optionally substituted, or Z andR^(d), together with the atoms to which they are bonded, form acycloalkyl or heterocycloalkyl group, where Z and R^(d) are as definedabove except for moieties that cannot form the cycloalkyl orheterocycloalkyl group, or Z and Z¹, together with the atoms to whichthey are bonded, form a cycloalkyl or heterocycloalkyl group, where Zand Z¹ are as defined above (except for moieties that cannot form thecycloalkyl or heterocycloalkyl group); or a prodrug, pharmaceuticallyacceptable salt, pharmaceutically active metabolite, or pharmaceuticallyacceptable solvate thereof.
 12. A compound, prodrug, pharmaceuticallyacceptable salt, pharmaceutically active metabolite, or pharmaceuticallyacceptable solvate according to claim 11, having the formula:

wherein: R^(a3) and R^(c) are as defined in claim
 11. 13. A compound,prodrug, pharmaceutically acceptable salt, pharmaceutically activemetabolite, or pharmaceutically acceptable solvate according to claims11 or 12, wherein R^(a3) is a aryl, heterocycloalkyl, heteroaryl orarylaminocarbonyl group, wherein the aryl, heterocycloalkyl, heteroarylor arylaminocarbonyl group is unsubstituted or substituted with one ormore substituents independently selected from (C₁-C₄)alkyl, aryl, halo,hydroxyl, nitro, amino, di-(C₁-C₄)alkylamino (C₁-C₄)alkoxy,alkylenedioxy, aryloxy, where the (C₁-C₄)alkyl or aryl moieties thereofare unsubstituted or optionally substituted by one or more of(C₁-C₄)alkyl (except for alkyl), halo, (C₁-C₄)haloalkyl, (C₁-C₄)alkoxy,(C₁-C₄)haloalkoxy, alkylenedioxy groups.
 14. A compound, prodrug,pharmaceutically acceptable salt, pharmaceutically active metabolite, orpharmaceutically acceptable solvate according to claims 11 or 12,wherein R^(a3) is a phenyl or phenylaminocarbonyl group, where thephenyl group or phenyl moiety of the phenylaminocarbonyl group isunsubstituted or substituted with one or more substituents independentlyselected from (C₁-C₄)alkyl, halo, hydroxyl, nitro, (C₁-C₄)alkoxy andalkylenedioxy.
 15. A compound, prodrug, pharmaceutically acceptablesalt, pharmaceutically active metabolite, or pharmaceutically acceptablesolvate according to claims 11 or 12, wherein R^(a3) is a phenyl orphenylaminocarbonyl group, where the phenyl group or phenyl moiety ofthe phenylaminocarbonyl group is unsubstituted or substituted with oneor more substituents independently selected from methyl, halo, hydroxyl,nitro, methoxy, and alkylenedioxy.
 16. A compound of formula:

wherein: R^(a4) is an aryloxy, heteroaryloxy, alkyloxy, cycloalkyloxy,heterocycloalkyloxy, aryl, cycloalkyl, or heteroaryl group, where thearyloxy, heteroaryloxy, alkyloxy, cycloalkyloxy, heterocycloalkyloxy,aryl, cycloalkyl, or heteroaryl group is unsubstituted or substitutedwith one or more suitable substituents; and R^(c) is a substituenthaving the formula:

wherein: R^(f) and R^(g) are each independently H or lower alkyl; m is 0or 1; p is an integer of from 0 to 5; A₁ is CH or N; when p is 1, 2, 3,4, or 5, A₂ is C(R^(h))(R^(i)), N(R^(j)), S, S(O), S(O)₂, or O, and whenp is 0, A₂ is C(R^(h))(R^(i))(R^(j)), N(R^(i))(R^(j)), S(R^(i)),S(O)(R^(i)), S(O)₂(R^(i)), or O(R^(i)), where each R^(h), R^(i) andR^(j) is independently H or a lower alkyl group; each A₃ present isindependently C(R^(h))(R^(i)), N(R^(j)), S, S(O), S(O)₂, or O; whereeach R^(h), R^(i) and R^(j) is independently H or lower alkyl; when p is1, 2, 3, 4, or 5, A₄ is N(R^(k)), C(R^(h))(R^(i)), or O; and when p is0, A₄ is N(R^(k))(R^(l)), C(R^(h))(R^(i))(R^(j)), and O(R^(l)), whereeach R^(h), R^(i) and R^(j) is independently H or lower alkyl, eachR^(k) is H, alkyl, aryl, or acyl, and each R^(l) is H, alkyl, or aryl;provided that no more than two heteroatoms occur consecutively in theabove-depicted ring formed by A₁, (A₂)_(m), (A₃)_(p), A₄, and C═O, whereeach dotted line in the ring depicts a single bond when A₂ is presentand a hydrogen atom when A₂ is absent; R^(d) is H, halogen, hydroxyl oran alkyl, alkoxy or alkylthio group, where the alkyl, alkoxy oralkylthio group is unsubstituted or substituted with one or moresuitable substituents; R^(b) is H or an alkyl group, unsubstituted orsubstituted with one or more suitable substituents; R^(c) is H, halogen,hydroxyl or an alkyl, alkoxy or alkylthio group, where the alkyl, alkoxyor alkylthio group is unsubstituted or substituted with one or moresuitable substituents; Z and Z¹ are each independently H, F, an alkyl,cycloalkyl, heterocycloalkyl, aryl or heteroaryl group, where the alkyl,cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is unsubstitutedor substituted with one or more suitable substituents, —C(O)R^(n)—CO₂R^(n) —CN, —C(O)NR^(n)R^(o), —C(O)NR^(n)R^(o), —C(S)R^(n),—C(S)OR^(n) —C(S)NR^(n)R^(o), —C(═NR⁷)R^(o), —C(═NR^(n))OR^(o), —NO₂,—SOR^(o), —SO₂R^(n), —SO₂NR^(n)R^(o), —SO₂(NR^(n))(OR^(o)), —SONR^(n),—SO₃R^(n), —PO(OR^(n))₂, —PO(OR^(n))(OR^(o)), —PO(NR^(n)R^(o))(OR^(p)),—PO(NR^(n)R^(o))(NR^(p)R^(q)), —C(O)NR^(n)NR^(o)R^(p),—C(S)NR^(n)NR^(o)R^(p), where R^(n), R^(o), R^(p) and R^(q) are eachindependently H or an alkyl, cycloalkyl, aryl, heterocycloalkyl, acyl orthioacyl group, where the alkyl, cycloalkyl, aryl, heterocycloalkyl,acyl or thioacyl group is unsubstituted or substituted with one or moresuitable substituents, or where any two of the R^(n), R^(o), R^(p) andR^(q), taken together with the atoms to which they are bonded, form aheterocycloalkyl group, which may be optionally substituted, or Z andR^(d), together with the atoms to which they are bonded, form acycloalkyl or heterocycloalkyl group, where Z and R^(d) are as definedabove except for moieties that cannot form the cycloalkyl orheterocycloalkyl group, or Z and Z¹, together with the atoms to whichthey are bonded, form a cycloalkyl or heterocycloalkyl group, where Zand Z¹ are as defined above (except for moieties that cannot form thecycloalkyl or heterocycloalkyl group); or a prodrug, pharmaceuticallyacceptable salt, pharmaceutically active metabolite, or pharmaceuticallyacceptable solvate thereof.
 17. A compound, prodrug, pharmaceuticallyacceptable salt, pharmaceutically active metabolite, or pharmaceuticallyacceptable solvate according to claim 16, wherein R^(a4) is an aryloxy,heteroaryloxy, (C₁-C₄)alkoxy, (C₃-C₈)cycloalkoxy, heterocycloalkyloxy,(C₃-C₈)cycloalkyl, heteroaryl or (C₁-C₄)alkoxycarbonyl group, whereinthe aryloxy, heteroaryloxy, (C₁-C₄)alkoxy, (C₃-C₈)cycloalkoxy,heterocycloalkyloxy, (C₃-C₈)cycloalkyl, heteroaryl or(C₁-C₄)alkoxycarbonyl group is unsubstituted or substituted with one ormore substituents independently selected from (C₁-C₄)alkyl, aryl,(C₃-C₈)cycloalkyl, heterocycloalkyl, heteroaryl, halo, hydroxyl,(C₁-C₄)alkoxy, alkylenedioxy, aryloxy, (C₃-C₈)cycloalkoxy, heteroaryloxyand (C₁-C₄)alkoxycarbonyl, where the (C₁-C₄)alkyl, aryl,(C₃-C₈)cycloalkyl, heterocycloalkyl, heteroaryl moieties thereof areoptionally substituted by one or more of (C₁-C₄)alkyl (except foralkyl), halo, (C₁-C₄)haloalkyl, (C₁-C₄)alkoxy, (C₁-C₄)haloalkoxy,alkylenedioxy, aryl or heteroaryl, where the aryl or heteroaryl isunsubstituted or substituted with one or more substituents independentlyselected from alkyl, haloalkyl, alkylenedioxy, nitro, amino,hydroxamino, alkylamino, dialkylamino, halo, hydroxyl, alkoxy,haloalkoxy, aryloxy, mercapto, alkylthio or arylthio groups.
 18. Acompound, prodrug, pharmaceutically acceptable salt, pharmaceuticallyactive metabolite, or pharmaceutically acceptable solvate according toclaim 16, wherein R^(a4) is a phenoxy, or (C₁-C₄)alkoxycarbonyl group,wherein the phenyl moiety of the phenoxy group is unsubstituted orsubstituted with one or more substituents independently selected fromhalo and (C₁-C₄)alkoxy.
 19. A compound, prodrug, pharmaceuticallyacceptable salt, pharmaceutically active metabolite, or pharmaceuticallyacceptable solvate according to any one of claims 1, 6, 11 or 16,wherein: A₁ is CH or N; A₂ is C(R^(h))(R^(i)), N(R^(j)), S, S(O), S(O)₂,or O; where each R^(h), R^(i) and R^(j) is independently H or loweralkyl; each A₃ present is independently C(R^(h))(R^(i)), N(R^(j)), S,S(O), S(O)₂, or O; where each R^(h), R^(i) and R^(j) is independently Hor lower alkyl; when p is 1, 2, 3, 4, or 5, A₄ is N(R^(k)),C(R^(h))(R^(i)), or O; and when p is 0, A₄ is N(R^(k))(R^(l)),C(R^(h))(R^(i))(R^(j)), and O(R^(l)), where each R^(h), R^(i) and R^(j)is independently H or lower alkyl, each R^(k) is H, alkyl, aryl, oracyl, and each R^(l) is H, alkyl, or aryl; provided that no more thantwo heteroatoms occur consecutively in the above-depicted ring formed byA₁, (A₂)_(m), (A₃)_(p), A₄, and C═O, where each dotted line in the ringdepicts a single bond when A₂ is present and a hydrogen atom when A₂ isabsent; Z and Z¹ are independently H, F, a unsubstituted or substitutedalkyl group, cycloalkyl group, heterocycloalkyl group, aryl group orheteroaryl group, —C(O)R^(n), —CO₂R^(n), —CN, —C(O)NR^(n)R^(o),—C(O)NR^(n)OR^(o), —C(S)R^(n), —C(S)NR^(n)R^(o), —NO₂, —SOR^(o),—SO₂R^(n), —SO₂NR^(n)R^(o), —SO₂(NR^(n))(OR^(o)), —SONR^(n), —SO₃R^(n),—PO(OR^(n))₂, —PO(OR^(n))(OR^(o)), —PO(NR^(n)R^(o))(OR^(p)),—PO(NR^(n)R^(o))(NR^(p)R^(q)), —C(O)NR^(n)NR^(o)R^(p),—C(S)NR^(n)NR^(o)R^(p), where each R^(n), R^(o), R^(p) and R^(q) areindependently H or an alkyl, cycloalkyl, aryl, heterocycloalkyl, acyl orthioacyl group, where the alkyl, cycloalkyl, aryl, heterocycloalkyl,acyl or thioacyl group is unsubstituted or substituted with one or moresuitable substituents, or where any two of the R^(n), R^(o), R^(p) andR^(q), taken together with the atoms to which they are bonded, form aheterocycloalkyl group, which may be optionally substituted, form aheterocycloalkyl group, provided that Z and Z¹ are not both H; or Z andR^(d), together with the atoms to which they are bonded, form acycloalkyl or heterocycloalkyl group, where Z and R^(d) are as definedabove except for moieties that cannot form the cycloalkyl orheterocycloalkyl group; or Z and Z¹, together with the atoms to whichthey are bonded, form a cycloalkyl or heterocycloalkyl group, where Zand Z¹ are as defined above except for moieties that cannot form thecycloalkyl or heterocycloalkyl group.
 20. The compound according toclaims 1, 6, 11 or 16, having antipicornaviral activity corresponding toan EC₅₀ less than or equal to 100 μM in an H1-HeLa cell culture assay.21. A pharmaceutical composition comprising: a therapeutically effectiveamount of at least one antipicornaviral agent selected from compounds,prodrugs, pharmaceutically acceptable salts, pharmaceutically activemetabolites, and pharmaceutically acceptable solvates defined in claims1, 6, 11 or 16; and a pharmaceutically acceptable carrier, diluent,vehicle, or excipient.
 22. A method of treating a mammalian diseasecondition mediated by picornaviral protease activity, comprisingadministering to a mammal in need thereof a therapeutically effectiveamount of at least one compound, prodrug, pharmaceutically acceptablesalt, pharmaceutically active metabolite, or pharmaceutically acceptablesolvate defined in claims 1, 6, 11 or
 16. 23. A method of inhibiting theactivity of a picornaviral 3C protease, comprising contacting thepicornaviral 3C protease with an effective amount of at least onecompound, prodrug, pharmaceutically acceptable salt, pharmaceuticallyactive metabolite, or pharmaceutically acceptable solvate defined inclaims 1, 6, 11 or 16,.
 24. The method as defined in claim 23, whereinthe picornaviral 3C protease is a rhinoviral protease.
 25. A compoundselected from the group:4S-[(naphthalene-2-carbonyl)-amino]-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoicacid ethyl ester;4S-[(naphthalene-2-carbonyl)-amino]-5-(2-oxo-pyrrolidin-3-R-yl)-pent-2-enoicacid ethyl ester;4S-[3-(3-bromo-phenyl)-acryloylamino]-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoicacid ethyl ester;N-[3-ethoxycarbonyl-1S-(2-oxo-pyrrolidin-3R-ylmethyl)-ally]-terephthalamicacid methyl ester;4S-[3-(3,4-dimethoxy-phenyl)-acryloylamino]-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoicacid ethyl ester;4S-[(5-bromo-pyridine-3-carbonyl)-amino]-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoicacid ethyl ester;4S-[(3-hydroxyquinoxaline-2-carbonyl)-amino]-5-(2-oxopyrrolidin-3S-yl)-pent-2-enoicacid ethyl ester;4S-[(5-ethyl-1H-indole-2-carbonyl)-amino]-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoicacid ethyl ester;4S-(3-benzo[1,3]dioxol-5-yl-acryloylamino)-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoicacid ethyl ester;4-[(1H-benzoimidazole-2-carbonyl)-amino]-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoicacid ethyl ester;4S-[3-(4-chloro-phenyl)-acryloylamino]-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoicacid ethyl ester;5-(2-oxo-pyrrolidin-3S-yl)-4S-(3-p-tolyl-acryloylamino)-pent-2-enoicacid ethyl ester;4S-[(3-acetyl-2-phenyl-thiazolidine-4-carbonyl)-amino]-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoicacid ethyl ester;4S-[(5-bromo-benzofuran-2-carbonyl)-amino]-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoicacid ethyl ester;4S-[3-(4-nitro-phenyl)-acryloylamino]-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoicacid ethyl ester;4S-[3-(methoxy-phenyl)-acryloylamino]-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoicacid ethyl ester;4S-[3-(3-hydroxy-phenyl)-acryloylamino]-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoicacid ethyl ester;4S-[(6,7-dimethoxy-naphthalene-2-carbonyl)-amino]-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoicacid ethyl ester;4S-[(5,6-dimethoxy-1-methyl-indole-2-carbonyl)-amino]-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoicacid ethyl ester;4S-[(5-bromo-1H-indole-2-carbonyl)-amino]-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoicacid;4S-[(5-bromo-1-methyl-indole-2-carbonyl)-amino]-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoicacid ethyl ester;4S-[(3-acetylamino-naphthalene-2-carbonyl)-amino]-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoicacid ethyl ester;4S[3-(3-bromo-4-methyl-phenyl)-acryloylamino]-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoicacid ethyl ester;4S-[3-(1S-ethoxycarbonyl-3-methyl-butyl)-ureido]-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoicacid ethyl ester;6-carbamoyl-4S-[(naphthalene-2-carbonyl)-amino]-hex-2-enoic acid ethylester; 4S-[(benzo[b]thiophene-2-carbonyl)-amino]-6-carbamoyl-hex-2-enoicacid ethyl ester;6-carbamoyl-4S-(4-dimethylamino-benzylamino)-hex-2-enoic acid ethylester; 6-carbamoyl-4S-[(quinoxaline-2-carboxyl)-amino]-hex-2-enoic acidethyl ester; 6-carbamoyl-4S-(3-phenyl-acryloylamino)-hex-2-enoic acidethyl ester;4S-[3-(3-bromophenyl)-acryloylamino]-6-carbamoyl-hex-2-enoic acid ethylester; 6-carbamoyl-4S-[(quinoline-2-carbonyl)-amino]-hex-2-enoic acidethyl ester; 6-carbamoyl-4S-[(5-methyl-2-phenyl-2H-[1,2,3]triazole-4-carbonyl)-amino]-hex-2-enoic acid ethyl ester;4S-[(2-benzyl-5-tert-butyl-2H-pyrazole-3-carbonyl)-amino]-6-carbamoyl-hex-2-enoicacid ethyl ester; 4S-benzylamino-6-carbamoyl-hex-2-enoic acid ethylester; 6-carbamoyl-4S-(3,4-dichloro-benzoylamino)-hex-2-enoic acid ethylester; benzoicacid-2-[1S-2-carbamoyl-ethyl)-3-ethoxycarbonyl-allylcarbamoyl]-benzylester; 6-carbamoyl-4S-(2-phenethyl-benzoylamino)--hex-2-enoic acid ethylester; 6-carbamyl-4S-[(1H-indole-2-carbonyl)-amino]-hex-2-enoic acidethyl ester;4S-[(5-fluoro-1H-indole-2-carbonyl)-amino]-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoicacid ethyl ester;4S-[(5-chloro-1H-indole-2-carbonyl)-amino]-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoicacid ethyl ester;4S-[(5-methoxy-1H-indole-2-carbonyl)-amino]-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoicacid ethyl ester;4S-[(7-nitro-1H-indole-2-carbonyl)-amino]-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoicacid ethyl ester;4-[(5-methyl-1H-indole-2-carbonyl)-amino]-5-(2-oxo-pyrrolidin-3-yl)-pent-2-enoicacid ethyl ester;4S-[(6-chloro-2H-chromene-3-carbonyl)-amino]-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoicacid ethyl ester;4S-[(2-methyl-5-phenyl-furan-3-carbonyl)-amino]-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoicacid ethyl ester;4S-[(6-benzyloxy-5-methoxy-1H-indole-2-carbonyl)-amino]-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoicacid ethyl ester;4S-[(1H-indole-2-carbonyl)-amino]-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoicacid ethyl ester;4S-[3-(3-bromo-4-fluoro-phenyl)-acryloylamino]-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoicacid ethyl ester;4S-[3-(6-bromo-benzo[1,3]dioxol-5-yl)-acryloylamino]-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoicacid ethyl ester;5-(2-oxo-pyrrolidin-3S-yl)-4S-[3-(2,4,6-trimethyl-phenylcarbamoyl)-acryloylamino]-pent-2-enoicacid ethyl ester;4S-[(6-methyl-naphthalene-2-carbonyl)-amino]-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoicacid ethyl ester;4S-[(6-bromo-2H-chromene-3-carbonyl)-amino]-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoicacid ethyl ester;4S-[(7-bromo-naphthalene-2-carbonyl)-amino]-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoicacid ethyl ester;4S-[(7-hydroxy-naphthalene-2-carbonyl)-amino]-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoicacid ethyl ester;5-(2-oxo-pyrrolidin-3S-yl)-4S-[3-(2-phenoxy-phenyl)-ureido]-pent-2-enoicacid ethyl ester;4S-(3-naphthalen-1-yl)-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoic acidethyl ester;4S-[3-(3,5-diethoxy-phenyl)ureido]-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoicacid ethyl ester;4S-[3-(3,5-dimethyl-phenyl)-ureido]-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoicacid ethyl ester;6-carbamoyl-4S-[3-(1-ethoxycarbonyl-3-methylbutyl)-ureido]-hex-2-enoicacid ethyl ester;4S-[2-(3-methoxy-phenoxy)-acetylamino]-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoicacid ethyl ester;4S-[2-(3-chloro-phenoxy)-acetylamino]-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoicacid ethyl ester;4S-[2-(3,4-dichloro-phenoxy)-acetylamino]-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoicacid ethyl ester;4S-[2-(3-chloro-phenyl)-acetylamino]-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoicacid ethyl ester;4S-[3-(2,5-dibromo-phenyl)-acryloylamino]-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoicacid ethyl ester; 4S-[(6-hydroxy-naphthalene-2-carbonyl)-amino]-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoic acid ethyl ester;4S-[(6-bromo-7-methyl-2H-chromene-3-carbonyl)amino]-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoic acid ethyl ester;4S-[(2H-chromene-3-carbonyl)-amino]-5-2-oxopyrrolidin-3S-yl)-pent-2-enoic acid ethyl ester;4S-[(4-bromo-6-methyl-naphthalene-2-carbonyl)amino]-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoic acid ethyl ester;4S-[(3-amino-naphthalene-2-carbonyl)-amino]-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoicacid ethyl ester; and or a prodrug, pharmaceutically acceptable salt,pharmaceutically active metabolite, or pharmaceutically acceptablesolvate thereof.